Functional Significance of Genetic Polymorphisms in P-glycoprotein (MDR1, ABCB1) and Breast Cancer Resistance Protein (BCRP, ABCG2)

Drug Metab. Pharmacokinet. 27 (1): 85­105 (2012).

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

Review Functional Significance of Genetic Polymorphisms in P-glycoprotein (MDR1, ABCB1) and Breast Cancer Resistance Protein (BCRP, ABCG2) Ichiro I EIRI * Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk Summary: Recent pharmacogenomic/pharmacogenetic (PGx) studies have disclosed important roles for drug transporters in the human body. Changes in the functions of drug transporters due to drug/food interactions or genetic polymorphisms, for example, are associated with large changes in pharmacokinetic (PK) profiles of substrate drugs, leading to changes in drug response and side effects. This information is extremely useful not only for drug development but also for individualized treatment. Among drug transporters, the ATP-binding cassette (ABC) transporters are expressed in most tissues in humans, and play protective roles; reducing drug absorption from the gastrointestinal tract, enhancing drug elimination into bile and urine, and impeding the entry of drugs into the central nervous system and placenta. In addition to PK/pharmacodynamic (PD) issues, ABC transporters are reported as etiologic and prognostic factors (or biomarkers) for genetic disorders. Although a consensus has not yet been reached, clinical studies have demonstrated that the PGx of ABC transporters influences the overall outcome of pharmacotherapy and contributes to the pathogenesis and progression of certain disorders. This review explains the impact of PGx in ABC transporters in terms of PK/PD, focusing on P-glycoprotein and breast cancer resistance protein (BCRP). Keywords: pharmacogenomics; ABC transporters; P-glycoprotein (MDR1, ABCB1); breast cancer resistance protein (BCRP, ABCG2)

As in drug-metabolizing enzymes, naturally occurring polymorphisms have also been recognized in ABC transporter genes. Numerous PGx studies have examined associations between polymorphisms of the ABC transporter genes and ¤1¥ the pharmacokinetics ¤PK¥ of substrate drugs, ¤2¥ therapeutic responses including side effects, and ¤3¥ the etiology and prognosis of various disorders. The application of pharmacogenetics ¤PGx¥-based concepts to clinical studies is believed useful for not only understanding or describing large inter-individual differences in PK/pharmacodynamics ¤PD¥ profiles of drugs but also clarifying the net in vivo role of functionally unknown transporters in the human body. The 49 members of the human ABC superfamily have been divided into 7 subfamilies ¤A to G¥ based on sequence homology. The focus of the present review is P-glycoprotein/MDR1/ABCB1 and BCRP/ABCG2, because they have been investigated extensively. As the number of PGx studies for ABCB1 is so large, only reports published from

Introduction The many drug transporters identified over the last two decades have been classified into two superfamilies, the solute carrier ¤SLC¥ family and the ATP-binding cassette ¤ABC¥ protein family. ABC transporters have conserved catalytic domains for ATP hydrolysis and actively pump out ¤efflux¥ substrates from intracellular to extracellular compartments in an ATP-dependent fashion. P-glycoprotein/MDR1/ABCB1 and breast cancer resistance protein ¤BCRP¥/ABCG2 are well characterized ABC transporters. First identified as multidrug resistance proteins in cancer cells, these efflux transporters have since been found in various normal human tissues ¤Fig. 1¥. A number of preclinical and clinical studies have demonstrated that ABC transporters play important roles in intestinal absorption, hepatic distribution, and renal excretion of substrate drugs ¤Fig. 1¥.

Received August 24, 2011; Accepted November 7, 2011 J-STAGE Advance Published Date: November 29, 2011, doi:10.2133/dmpk.DMPK-11-RV-098 *To whom correspondence should be addressed: Ichiro IEIRI, Ph.D., Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Tel. +81-92-642-6656, Fax. +81-92-642-6660, E-mail: [email protected] 85

86

Ichiro IEIRI

Fig. 1. ABC transporters expressed in the human liver, kidney, and intestine BSEP: bile salt export pump, MRP: multidrug resistance-associated protein, BCRP: breast cancer resistance protein, P-gp: P-glycoprotein.

Fig. 2. Schematic representation of P-glycoprotein’s secondary structure with well known major synonymous and non-synonymous nucleotide substitutions at the corresponding amino acid position

Table 1. General features of drug transporters (substrates and inhibitors) Name

Abbreviation ¤Gene nomencalture¥

Substrates

Inhibitors

MDR1 ¤ABCB1¥

anticancers ¤docetaxel, etoposide, paclitaxel, topotecan, vinblastine¥, antihypertensives ¤diltiazem, losartan¥, antiarrhythmics ¤digoxin, verapamil¥, antivirals ¤indinavir, nelfinavir¥, antibiotics ¤erythromycin, sparfloxacin¥, immunosuppressants ¤cyclosporine, tacrolimus¥, others ¤cimetidine, fexofenadine, loperamide, phenytoin, morphine, ondansetron¥

amiodarone, amitriptyline, diltiazem, dipyridamole, phenothiazines, propafenone, propranolol, quinidine, spironolactone, tamoxifen

Breast cancer-resistance protein BCRP ¤ABCG2¥

epirubicin, topotecan, doxorubicin, daunorubicine, etoposide, SN-38, reserpine, sulfasaladine, gefitinib, imatinib, irinotecan, MTX, mitoxantrone, topotecan, ciprofloxacin, ofloxacin, norfloxacin, zidovudine, lamivudine, genestein, quercetin, pravastatin, rosuvastatin, prazosin, nitrofurantoin, cimetidine, estrone-3-sulfate, dehydroepiandrosterone sulfate, E217ÇG, dinitrophenyl-S-glutathione

cyclosporin A, tacrolimus, sirolimus, gefitinib, imatinib, naringenin, quercetin, genistein, 17Ç-estradiol, estrone, tamoxifen, reserpine, curcumin, dipyridamole, nicardipene, nitrendipene, nimodipene

P-glycoportein ¤P-gp¥

E217ÇG: 17-Ç-D-estradiol-glucuronide, MTX: methotrexate.

2006 to 2011 are covered in this review. The impact of genetic polymorphisms of ABCB1 reported before 2006 has been reviewed elsewhere.1®3¥ The scope of this review is strictly limited to observations from clinical studies. P-glycoprotein General features: P-glycoprotein, the ABCB1 ¤alternate name MDR1¥ gene product, is expressed in the small and large intestinal epithelium, adrenal gland, placenta ¤trophoblasts¥, kidney ¤the brush border of the renal tubule¥, liver ¤the canalicular membrane of the hepatocytes¥, pancreas ¤pancreatic ductile cells¥, and capillary endothelial cells of the brain and testes.4®8¥ Its tissue distribution and findings in knockout mice suggest that P-glycoprotein plays important roles in: the excretion of foreign xenobiotics and endogenous substrates via the canalicular membrane of hepatocytes into bile and via the brush border membrane of enterocytes and proximal tubules into the gut lumen and

urine, respectively;9,10¥ the blocking of the transfer of hydrophobic xenobiotics across the placenta;11¥ and prevention of the entry of substrates into the central nervous system as part of the blood-brain barrier.12®14¥ In summary, P-glycoprotein acts in defense of the human body. P-glycoprotein accepts a broad spectrum of structurally and functionally unrelated drugs ¤Table 1¥. Interestingly, there is a strong overlap in substrate specificity and tissue distribution between P-glycoprotein and cytochrome P450 3A4/5.15,16¥ The ABCB1 gene is located on chromosome 7 at q21, with 28 exons encoding a protein of 1,280 amino acids.17¥ Since the first evidence of the presence of naturally occurring polymorphisms in the human ABCB1 gene, which was reported by Mickley et al.,18¥ who found two SNPs in exon 21 ¤2677GhT¥ and 24 ¤2995GhA¥, numerous SNPs have been identified ¤Fig. 2¥.1,19®23¥ Among them, 1236ChT ¤rs1128503, exon 12¥, 2677GhT/A ¤rs2032582, exon 21¥,

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

87

Human ABCB1 and ABCG2 Gene Polymorphisms Table 2. Frequency of variants in ABCB1 and ABCG2 genes in 3 different ethnic populations Gene

Variant

dbSNP ID

%1517aThC %1459aGhA

AA substitution

European

rs28381796

0.047®0.081

0

0

rs12720464

0.186®0.329

0

0®0.027

0.037

0

ND

rs28746504

0.062

0.045

0.1®0.167

0.005

0

ND

%42a AhG

rs57806198

0.106

0

ND

%145ChG

rs34976462

0.032

0

ND

%129ThC

rs3213619

0.047®0.081

0.031®0.062

0.043®0.167

%1132a CCATChdel %1017aThC %824a ThC

ABCB1

61AhG 1199GhA

rs2229109

1236ThC

rs1128503

2677GhT 2677GhA

rs2032582

2956AhG 3421ThA 3435ChT

ABCG2

Frequency Asian

African

21AsnhAsp

0®0.017

0.08

0.025

400SerhAsn

0

0.021®0.2

0

0.312®0.333

0.523®0.614

0.750®1

893AlahSer

0.522®0.616

0.339®0.469

0®0.077

893AlahThr

0.152

0.042

0.021

986MethVal

0.005

ND

ND

1141SerhThr rs1045642

0

0

0.111

0.375®0.523

0.468®0.625

0®0.208 0.042®0.05

34GhA

rs2231137

12ValhMet

0.193®0.289

0®0.046

376ChT

rs72552713

126Glnhstop

0.009®0.017

0

0

421ChA

rs2231142

141GlnhLys

0.289®0.357

0.045®0.117

0®0.023

496ChG

rs1061017

166GlnhGlu

0®0.0111

0

0

616AhC

rs12721643

206IlehLeu

0

0

0

623ThC

rs1061018

208PhehSer

0.012®0.039

0

0.009 0

742ThC

rs3116448

248SerhPro

0

0

1000GhT

rs3201997

334Gluhstop

0

0

0

1322GhA

441SerhAsn

0.005

ND

ND

1465ThC

489PhehLeu

0.005®0.008

ND

ND

0.005

ND

ND

571PhehIle

0

0

0.022

506PhehSer 507PhehLeu

1515delC

508ValhLeu 509Methstop

1711ThA

rs9282571

1768AhT

rs34264773

590AsnhTyr

ND

0.074®0.098

0

1858GhA

rs34783571

620AsphAsn

0

0.008®0.0111

0

AA: amino acid, ND: no data.

and 3435ChT ¤rs1045642, exon 26¥ are well studied ¤Tables 2 and 3¥. 2677GhT/A is located on the intracellular side of P-glycoprotein after transmembrane region 10, resulting in an amino acid change from Ala at codon 893 to Ser/Thr. In contrast, 1236ChT and 3435ChT are synonymous. Interestingly, 2677GhT/A and 3435ChT are in linkage disequilibrium; h90% of Japanese,20¥ 60% of European American23¥ and 80% of Caucasian German24¥ individuals have both these SNPs. Thus, haplotype-oriented analysis has been taken into consideration in genotypephenotype studies. The allelic frequency distribution of SNPs is reported to be highly racially dependent ¤Table 2¥.1¥

Impact of SNPs on pharmacotherapy and their clinical utility as bio-markers: Since Hoffmeyer et al.19¥ first reported that 3435ChT was associated with significantly reduced intestinal P-glycoprotein expression in T/T homozygotes in comparison with subjects homozygous for the C allele ¤C/C¥, leading to higher steady-state plasma concentrations after the oral administration of digoxin, a remarkably large number of human studies have been done. However, as pointed out,1,25®28¥ observations are inconsistent even with the same probe drugs and among the same disease/racial populations. For example for digoxin, Sakaeda et al.29¥ and Kim et al.23¥ reported that the AUC tended to be

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

88

Ichiro IEIRI Table 3. Impact of ABCB1 (P-glycoprotein) polymorphisms on PK/PD/disorders Functional effect of the study

Gene marker ¤SNPs/haplotype¥

Others ¤e.g., Pharmaco- Therapeutic Side SNPs frequency and kinetics efficacy effects assay susceptibility¥

Drug

Population

Disease

Ref.

1236ChT, 2677GhT/A, 3435ChT

*

patient

nephrotic syndrome

74

1236ChT, 2677GhT/A, 3435ChT

*

patient

epilepsy

75

atorvastatin

patient

myalgia

76

3435ChT

*

*

1236ChT, 2677GhT/A, 3435ChT

*

valproate

patient

epilepsy

77

2677GhT/A, 3435ChT

*

oxycodone ¤iv¥

patient

postoperative pain

78

rs1045642 ¤3435ChT¥

*

radiochemotherapy

pateint

LAEC

79

3435ChT

*

colchicine

pateint

Behçetös syndrome

80

3435ChT

*

*

folic acid

pateint

congenital heart defect

81

*

5-Fu/capecitabine

pateint

neutropenia/handfoot syndrome

82

patient

AML

83

domperidone

patient

gastroparesis

84

1236ChT, 2677GhT/A, 3435ChT 3435ChT

*

61AhG, 1199GhA, 2677ThG/A, 3435ThC

*

*

2677GhT/A

*

paclitaxel

patient

85

1236ChT, 2677GhT/A, 3435ChT

*

cyclosporine

patient

heart transplantation 86

anti-cancer drugs

patient

ovarian cancer

87

efavirenz

patient

HIV

88

2677GhT/A, 3435ChT rs3842ThC, 3435ChT

*

3435ChT

*

second-line chemotherapy

patient

AGC

89

3435ChT

*

ticagrelor, clopidogrel

patient

ACS

90

3435ChT

*

clopidogrel

patient

ACS

91

*

ondansetron

patient

general anaesthesia

92

*

antidepressants

patient

depression

93

docetaxel

patient

breast cancer

94

morphine

patient

spinal anaesthesia

95

patient

breast cancer

96

patient

epilepsy

37

2677GhT/A, 3435ChT 3435ChT %129ThC, 61AhG, 1236ChT, 2677GhT/A, 3435ChT

* *

1236ChT, 2677GhT/A, 3435ChT

*

3435ChT

*

3435ChT 2677GhT/A, 3435ChT

*

antiepileptic drugs

*

2677GhT/A, 3435ChT

*

15 SNPs

*

1236ChT, 2677GhT/A, 3435ChT

risperidone

patient

psychosis

97

organochlorine insecticides

patient

PD

98

antidepressants

patient

depression

99

patient

CRC

100

bortezomib, doxorubicin

patient

myeloma

101

cyclosporine

patient

kidney transplants

102

atazanavir

patient

hyperbilirubinemia

103

*

3435ChT

*

1236ChT, 2677GhT/A, 3435ChT

*

2677GhT/A, 3435ChT

*

1236ChT, 2677GhT/A, 3435ChT

*

levosulpiride

HV

104

1236ChT, 2677GhT/A, 3435ChT

*

risperidone

HV

105

1236ChT, 2677GhT/A, 3435ChT

*

imatinib

patient

CML

106

3435ChT

*

guanfacine

patient

PDD, hyperactivity

107

Continued on next page:

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

89

Human ABCB1 and ABCG2 Gene Polymorphisms

Continued: Functional effect of the study Gene marker ¤SNPs/haplotype¥

Others ¤e.g., Pharmaco- Therapeutic Side SNPs frequency and kinetics efficacy effects assay susceptibility¥

1236ChT, 2677GhT/A, 3435ChT

*

1236ChT, 3435ChT

*

1236ChT, 3435ChT

1236ChT, 2677GhT/A, 3435ChT

*

2677GhT/A, 3435ChT

*

cancers

108

HIV ¤children¥

109

111

HV

antiepileptic drugs

patient

epilepsy

*

cyclosporine

patient

heart transplantation 112

*

risperidone

patient

schizophrenia

113

nevirapine

patient

hepatotoxicity

114

* *

paclitaxel *

*

patient

AGC

115

CRC

116

azithromycin

HV

117 118

*

simvastatin

patient

3435ChT

*

cetuximab plus irinotecan

patient

2677GhT/A, 3435ChT

*

oxycodone

HV

*

3435ChT

*

3435ChT

* *

110

patient

1236ChT, 2677GhT/A, 3435ChT

1236ChT, 2677GhT/A, 3435ChT

Ref.

rebamipide

3435ChT, rs3789243 2677GhT/A, 3435ChT

patient

Disease

*

3435ChT 3435ChT

Population

3-aminopyridine-2-carboxaldehyde patient thiosemicarbazone

*

2677GhT/A, 3435ChT

Drug

IRLMCRC

119 120

patient

male infertility

121

periconceptional medication

patient

cleft palate

122

tacrolimus

patient

paediatric liver 123 transplant recipients

2677GhT/A, 3435ChT

*

verapamil

HV

3435ChT

*

tacrolimus

patient

1236ChT, 2677GhT/A, 3435ChT

*

4 statins

HV

sunitinib

patient

cancers

127

clozapine

patient

psychosis

128

patient

advanced breast carcinoma

129

patient

cannabis dependence 130 risk

1236ChT, 2677GhT/A, 3435ChT 1236ChT, 2677GhT/A, 3435ChT

* *

3435ChT

*

FAC regimen

3435ChT 1236ChT, 2677GhT/A, 3435ChT

* *

1236ChT, 2677GhT/A, 3435ChT

*

3435ChT

*

3435ChT

*

3435ChT *

3435ChT

*

1236ChT, 2677GhT/A, 3435ChT

*

HV

5-fluorouracil/leucovorin

patient

CRC

132

patient

PCM

133

patient

cancers

134

patient

ulcerative colitis

135

patient

LDLT

136

lansoprazole

HV

intragastric pH

137

HAART regimens

patient

irinotecan, cisplatin

tacrolimus *

1236ChT, 2677GhT/A, 3435ChT

*

3435ChT

*

2677GhT/A, 3435ChT

anthracycline *

*

126

cloxacillin

*

2677GhT/A, 3435ChT

3435ChT

*

124 liver transplantation 125

telmisartan

131

138

patient

PD

139

patient

breast cancer

140

patient

Crohnös disease

141

HV

142

Continued on next page:

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

90

Ichiro IEIRI

Continued: Functional effect of the study Gene marker ¤SNPs/haplotype¥

Others ¤e.g., Pharmaco- Therapeutic Side SNPs frequency and kinetics efficacy effects assay susceptibility¥

Drug

Population

Disease

Ref.

3435ChT

*

indinavir

patient

143

2677GhT/A, 3435ChT

*

voriconazole

HV

144

129ChT, 1236ChT, 2677GhT/A, 3435ChT

*

1236ChT, 2677GhT/A, 3435ChT

*

1236ChT, 2677GhT/A, 3435ChT

*

2677GhT/A, 3435ChT

*

*

1236ChT, 2677GhT/A, 3435ChT

ulcerative colitis

145

tacrolimus, cyclosporine

patient

renal transplant recipients

146

cyclosporine

patient

renal transplant patients

147

paclitaxel

patient

metastatic breast cancer

148

patient

SLE

149

*

3435ChT

*

1236ChT, 2677GhT/A, 3435ChT

*

losartan

2677GhT/A, 3435ChT 1236ChT, 2677GhT/A, 3435ChT

patient

*

*

* *

3435ChT 1236ChT, 2677GhT/A, 3435ChT

*

HV

150

digoxin

HV

olanzapine, isperidone

patient

schizophrenia

152

151

risperidone

patient

schizophrenia

153

cyclosporine

patient

gingival overgrowth 154

temozolomide

patient

glioblastoma

155 156

3435ChT

*

patient

gastric cancer, peptic ulcers

1236ChT, 2677GhT/A, 3435ChT

*

patient

myeloma

157

docetaxel

patient

AIPC

158

dicloxacillin

HV & patient

cystic fibrosis

159

1236ChT, 2677GhT/A, 3435ChT 2677GhT/A, 3435ChT

*

*

*

2677GhT/A, 3435ChT

*

paroxetine

patient

major depression

160

1236ChT, 2677GhT/A, 3435ChT

*

imatinib

patient

CML

161

renal disease

162

1236ChT, 2677GhT/A, 3435ChT

*

cyclosporine

patient

1236ChT, 2677GhT/A, 3435ChT

*

valacyclovir

HV

2677GhT/A

*

rs1045642, rs2032582, rs1128503

*

methadone

163

HV & patient

obesity

164

patient

opiate dependence

165

2677GhT/A, 3435ChT

*

patient

multiple myeloma

166

2677GhT/A, 3435ChT

*

patient

AlCP & Alc

167

breast cancer

168

1236ChT, 2677GhT/A, 3435ChT

*

doxorubicin

patient

2677GhT/A, 3435ChT

*

verapamil

HV

169

1236ChT, 2677GhT/A, 3435ChT

*

digoxin

patient

170

2677GhT/A, 3435ChT

*

phenobarbital

patient

generalized epilepsy 171

morphine

patient

cancer

patient

steroid-induced ONF 173

2677GhT/A

*

2677GhT/A, 3435ChT 3435ChT

* *

*

*

172

valproic acid

patient

bipolar disorder

174

3435ChT

*

carbamazepine

patient

epilepsy

175

2677GhT/A, 3435ChT

*

paroxetine

patient

major depression

176

Continued on next page:

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

91

Human ABCB1 and ABCG2 Gene Polymorphisms

Continued: Functional effect of the study Gene marker ¤SNPs/haplotype¥

Others ¤e.g., Pharmaco- Therapeutic Side SNPs frequency and kinetics efficacy effects assay susceptibility¥

Drug

rs2032583, rs2235040

*

paroxetine

1236ChT, 2677GhT/A, 3435ChT

*

paroxetine

3435ChT

*

morphine

Population

Disease

Ref.

major depression

177

patient

major depression

178

patient

pain relief

179

3435ChT

*

patient

hyperthyroidism ¤T3¥ 180

3435ChT

*

patient

UADT cancers

181

2677GhT/A, 3435ChT

*

vinorelbine

patient

NSCLC

182

1199GhA

*

paclitaxel

patient

ovarian cancer

183

3435ChT

*

triple therapy

patient

Helicobacter pylori infection

184

patient

IBD

185

2677GhT/A, 3435ChT

*

3435ChT

*

colchicine

patient

FMF

186

2677GhT/A

*

platinum and taxan

patient

ovarian cancer

40

1236ChT, 2677GhT/A, 3435ChT

*

paclitaxel and carboplatin

patient

overian cencer

41

%2352 GhA, %934AhG, %692ThC, 3435ChT

*

patient

childhood ALL

187

3435ChT

*

patient

breast cancer

188

2677GhT/A, 3435ChT

*

prolactin concentrations

patient

schizophrenia

189

1236ChT, 2677GhT/A, 3435ChT

*

indoor insecticide exposure

patient

childhood ALL

190

imatinib

patient

GST or CML

191

patient

multiple myeloma

192

recurrence of HCC

patient

liver transplantation 193

1236ChT, 2677GhT/A, 3435ChT

*

3435ChT

*

1236ChT, 2677GhT/A, 3435ChT

*

2677GhT/A

*

gabapentin

HV

194

2677GhT/A, 3435ChT

*

atazanavir, lopinavir

patient

195

patient

endometrial cancer

196

azathioprine

patient

Crohnös disease

197

patient

IBD

198

fentanyl

patient

spinal anesthesia

199

lansoprazole

patient

renal transplant recipients

200

methotrexate

patient

rheumatoid arthritis 201

methadone

patient

opioid related conditions

202

atazanavir

patient

HIV infection

203

patient

lung cancer

204

olanzapine

patient

schizophrenia

205

clopidogrel

patient

coronary artery disease

206

patient

B-CLL

207

patient

schizophrenia

208

3435ChT

*

2677GhT/A, 3435ChT

*

2677GhT/A, 3435ChT

*

1236ChT, 2677GhT/A, 3435ChT 3435ChT

* *

3435ChT

*

5SNPs 3435ChT

* *

2677GhT/A, 3435ChT

*

2677GhT/A, 3435ChT 3435ChT

*

*

*

3435ChT 1236ChT, 2677GhT/A, 3435ChT

*

* *

risperidone

Continued on next page:

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

92

Ichiro IEIRI

Continued: Functional effect of the study Gene marker ¤SNPs/haplotype¥

Others ¤e.g., Pharmaco- Therapeutic Side SNPs frequency and kinetics efficacy effects assay susceptibility¥

1236ChT, 2677GhT/A, 3435ChT

*

Drug

Population

olanzapine

patient

1236ChT, 2677GhT/A, 3435ChT

*

mefloquine

HV

3435ChT

*

paclitaxel

patient

3435ChT

*

3435ChT 2677GhT/A, 3435ChT

* *

3435ChT

*

2677GhT/A, 3435ChT

*

*

Disease

schizophrenia

Ref.

209 210

neuropathy, neutropenia

211

methotrexate plus methylprednisopatient lone/ sulfasalazine

rheumatoid arthritis 212

nevirapine

patient

hepatotoxicity

amlodipine

HV

AEDs

patient

epilepsy

215

patient

SCT

216

PBC

217

*

213 214

2677GhT/A, 3435ChT

*

budesonide

patient

1236ChT, 2677GhT/A, 3435ChT

*

sparfloxacin

HV

etoposide and cisplatin

patient

SCLC

219

2677GhT/A, 3435ChT

*

2677GhT/A, 3435ChT

*

218

paclitaxel

patient

ovarian cancer

220

2677GhT/A, 3435ChT

*

calcium antagonists

patient

gingival hyperplasia

221

3435ChT

*

atazanavir

patient

hyperbilirubinemia

222

1®3¥

This table includes ABCB1 PGx studies reported from 2006 to 2011 in scientific journals. Human studies before 2006 have been summarized previously. LAEC: locally advanced esophageal cancer, ALL: acute lymphocytic leukemia, AGC: advanced gastric cancer, ACS; acute coronary syndromes, PD; Parkinson disease, CRC: colorectal cancer, CML: chronic myeloid leukemia, PDD: pervasive developmental disorder, IRLMCRC: irinotecan refractory liver metastatic colorectal cancer, FAC: 5-fluorouracil/doxorubicin/cyclophosphamide, PCM: plasma cell myeloma, LDLT: living-donor liver transplant, HAART: highly active antiretroviral therapy, SLE: systemic lupus erythematosus, AIPC: androgen-independent prostate cancer, AlCP: chronic alcoholic pancreatitis, Alc: alcoholic patients, ONF: osteonecrosis of femoral head, UADT: upper aerodigestive tract, SCLC: small cell lung cancers, NSCLC: non-small cell lung cancers, IBD: inflammatory bowel disease, FMF: familial Mediterranean fever, GST: gastrointestinal stromal tumor, HCC: hepatocellular carcinoma, B-CLL: B-cell chronic lymphocytic leukemia, AED: antiepileptic drugs, SCT: allogeneic stem cell transplantation, PBC: primary biliary cirrhosis.

lower in T/T than C/C homozygotes; which is in complete contrast to the findings of Hoffmeyer et al.19¥ and Kurata et al.30¥ Although cyclosporine is a good substrate for Pglycoprotein, similar to digoxin, results vary as to the effects of 3435ChT and 2677GhT/A polymorphisms on its pharmacokinetics ¤Table 3¥. One meta-analysis, based on 14 studies and 1,036 patients, failed to find a definitive impact of 3435ChT on the pharmacokinetics of cyclosporine.31¥ Numerous studies have also investigated the influence of polymorphisms on side effects of and clinical responses to important drugs, especially anti-neoplastic agents, antidepressants, and immunosuppressants ¤Table 3¥. Besides the well-known SNPs in the ABCB1 gene ¤e.g., 3435ChT and 2677GhT/A¥, two intronic SNPs, rs2032583 and rs2235040, were shown to be predictors of treatment outcome in patients taking paroxetine. However, some studies have failed to find a significant association between the 3435ChT polymorphism and treatment outcome, either for antidepressant plasma levels or clinical efficacy.32®34¥ About one-third of newly treated epileptic patients do not respond adequately to antiepileptic drugs ¤AEDs¥.35¥ In order to understand drug-resistant epilepsy, the association

between 3435ChT and pharmacoresistance to AEDs has been studied ¤Table 3¥. Since the first PGx study,36¥ at least 21 replicative studies have been conducted; however, only 9 had positive results.37¥ To date, a number of meta-analysisbased studies have been reported: ¤1¥ 11 case-control studies including 3,371 patients,38¥ ¤2¥ 3 studies with 1,064 patients,39¥ and ¤3¥ 22 association studies with 3231 drugresistant patients and 3,524 drug-positive patients and healthy controls.37¥ Interestingly, none of these studies found an association between 3435ChT and the risk of drug-resistance. Thus, the contribution of 3435ChT to the pharmacoresistance to AEDs in epilepsy may need to be reconsidered. Paclitaxel and docetaxel are routinely used in the treatment of breast, ovarian and lung cancers and are major substrates for P-glycoprotein. Numerous studies including some large clinical trials ¤e.g., the SCOTROC1 phase III trial40¥ and the Australian Ovarian Cancer Study41¥¥ have investigated associations between three well known SNPs and clinical response, toxicity or survival ¤Table 3¥. However, a definitive conclusion has yet to be reached. Since P-glycoprotein transports various endogenous compounds, associations between ABCB1 polymorphisms and susceptibility to or the etiology of disease are of interest.

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

Human ABCB1 and ABCG2 Gene Polymorphisms

To date, the following diseases have been studied: Parkinsonös disease, epilepsy, depression, SLE, inflammatory bowel diseases ¤ulcerative colitis and Crohnös disease¥, cancers ¤leukemia, colon cancer, renal epithelial tumors and glioma¥, liver and renal diseases ¤cirrhosis and nephritic syndrome¥, gingival hyperplasia, rheumatoid arthritis and hypertension ¤Table 3¥. As described previously, definitive conclusions remain to be reached for most of these diseases. The question arises as to why genotyping/phenotyping relationships differ among studies. Numerous kinds of drugs/compounds have previously been used as a probe ¤or test¥ drug in the ABCB1/PGx studies. However, contribution of P-glycoprotein to the overall pharmacokinetics of each drug is unknown in the human body in the most cases. In other words, the substrate specificity, which means that whether P-glycoprotein is the only transporter involved in its pharmacokinetics or not, is an essential issue for the PGx study. For example for digoxin, the most frequently used test drug for ABCB1/PGx study, has recently been reported to be a substrate of a sodium-dependent transporter, in addition to P-glycoprotein.42¥ Furthermore, a recent study indicated that fexofenadine, another famous probe drug, is a multiple-substrate for drug transporters such as polymorphic MRP2 and OATP2B1.43¥ Since the nature of dual- or multiple-transporters-mediated transporting may mask the net in vivo function of P-glycoprotein, a suitable specific probe drug should be used to test the genotyping/ phenotyping relationship correctly. Some investigators including our group measured the brain distribution of a model P-glycoprotein substrate, the calcium-channel blocker ª11C«verapamil, using positron emission tomography ¤PET¥.44,45¥ They evaluated P-glycoprotein function as a úgatekeeperû ¤i.e., protection of highly sensitive tissue brain from xenobiotics¥ in the blood brain barrier. These studies shared the results that the ABCB1 polymorphisms do not affect the brain distribution of verapamil. PET has sensitivity to detect tissue distribution of substrates in the lower picomolar range, suggesting that the significance of SNPs, even in the haplotypes, in the ABCB1 gene on the pharmacokinetics of substrate drugs, if any, is low. Breast Cancer Resistance Protein ¤BCRP¥ General features: Breast cancer resistance protein ¤BCRP¥, the ABCG2 gene product, is highly expressed in various tissues and its localization and vectorial movement in the human body are similar to those of P-glycoprotein. Thus, its physiological function may be the regulation of the intestinal absorption and biliary secretion of substrates, and protection of the fetus and brain from toxic xenobiotics. The ABCG2 gene is located at 4q22 and encodes a 72-kDa membrane protein composed of 655 amino acids. Unlike most other ABC transporters, which have two nucleotidebinding domains ¤NBDs¥ and twelve transmembrane domains ¤TMDs¥, BCRP is a half-transporter ¤i.e., one

93

Fig. 3. Schematic representation of BCRP’s secondary structure with well known major synonymous and non-synonymous nucleotide substitutions at the corresponding amino acid position

NBD and six TMDs¥ and may form a homodimer when acting as a drug transporter.46®49¥ BCRP transports negatively or positively charged compounds including organic anions and sulfate conjugates ¤Table 1¥. There is considerable, but not complete, overlap in substrates with P-glycoprotein. Systematic analyses of the ABCG2 gene have been performed in various ethnic groups, and over 50 SNPs have been identified ¤Fig. 3¥.50®53¥ As with other transporters, the frequency of SNPs exhibits inter-ethnic differences. Notably, two non-synonymous mutations, 34GhA ¤12ValhMet in exon 2¥ and 421ChA ¤141GlyhLys in exon 5¥, are frequently observed in Asian rather than Caucasian or African American populations ¤Table 2¥. Interestingly, three nonsynonymous SNPs, 34GhA, 376ChT ¤126Glnhstop codon in exon 4¥, and 421ChA, occurred simultaneously; our data shows that G-C-C, G-C-A, A-C-C and G-T-C haplotype exist with their corresponding allelic frequencies of 46, 35, 18 and 1%, respectively.52¥ One base deletion was observed in exon 13 ¤1515Chdel¥ which was also associated with the stop codon, but was of low frequency in Japanese ¤Table 2¥.52¥ Impact of SNPs on pharmacotherapy and their clinical utility as bio-markers: Since the first human PGx study in 2004,54¥ associations between ABCG2 polymorphisms and ¤1¥ the PK of substrate drugs, ¤2¥ clinical responses, and ¤3¥ susceptibility to or the etiology of diseases have been examined ¤Table 4¥. The target SNP in most studies is the non-synonymous 421ChA ¤rs2231142,

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

94

Ichiro IEIRI Table 4. Impact of ABCG2 (BCRP) polymorphisms on PK/PD/disorders Functional effect of the study Gene marker ¤SNPs/haplotype¥

Pharmacokinetics

Therapeutic efficacy

%15622CgT or ¤1143ChT, %15622ChT¥ haplotype 421ChA

Side effects

SNPs assay

Others ¤e.g., frequency and susceptibility¥

* *

*

421ChA ¤141QhK, rs2231142¥

Drug

gefitinib

patient

A771726

HV

*

421ChA

*

Population

imatinib

Disease

NSCLC

Ref.

68 223

patient

gout

224

patient

CML

225

421ChA

*

patient

uric acid

226

421ChA ¤141QhK, rs2231142¥

*

patient

gout

227

patient

RA

228

421ChA, 914ChA

*

421ChA

*

421ChA

methotrexate

* *

346GhA, 421ChA, 1143ChT, 15994GhA

*

421ChA

*

421ChA

sunitinib

patient

RCC

70

rosuvastatin

patient

myocardial infarction

229

danusertib

patient

rosuvastatin

patient

hypercholesterolemia

231

patient

gout

232

NSCLC

*

376ChT, 421ChA

*

230

gefitinib

patient

421ChA

*

telatinib

patient

233

421ChA

*

3 statines

HV

234

rs2622604

*

irinitecan

patient

¤%15622C/T, 1143C/T¥ haplotype

*

sunitinib

patient

*

mitoxantrone

patient

multiple sclerosis

236

*

CML

237

12VhM, 141QhK 421ChA

myelosuppression

67

235 127

imatinib

patient

421ChA

*

sulfasalazine

HV

421ChA

*

erlotinib

patient

SCC

69

patient

gout

239

421ChA 421ChA

* *

12VhM, 141QhK

*

12VhM 421ChA

atorvastatin, rosuvastatin

HV

R-CHOP

patient

DLBCL

241

patient

ischemic stroke

242

patient

solid malignancies

243

patient

gout

73

patient

colorectal cancer

244

* *

421ChA

imatinib *

rs2622621, rs1481012

238

*

240

421ChA

*

nitrofurantoin

HV

245

421ChA

*

sulfasalazine

HV

246

421ChA

*

doxorubicin

patient

421ChA

*

sulfasalazine

HV

Q141K, V12M, Q126X

*

lamivudine

HV

34ChA, 421ChA 421ChA

* *

patient pitavastatin

HV

breast cancer

168 60 247

DLBCL

248 64

Continued on next page:

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

95

Human ABCB1 and ABCG2 Gene Polymorphisms

Continued: Functional effect of the study Gene marker ¤SNPs/haplotype¥

Pharmacokinetics

Therapeutic efficacy

421ChA

Side effects

SNPs assay

Others ¤e.g., frequency and susceptibility¥

*

Drug

Population

Disease

Ref.

gefitinib

patient

diarrhea, skin toxicity

66

docetaxel

patient

HRPC

249

*

rosuvastatin

HV

421ChA

*

9-nitrocamptothecin

patient

141QhK

*

topotecan

patient

421ChA 421ChA

*

421ChA 421ChA

* *

patient irinotecan

patient

59 refractory solid tumors

65 58

RCC

250 63

NSCLC: non-small cell lung cancer, CML: chronic myeloid leukemia, RA: rheumatoid arthritis, RCC: renal cell carcinoma, SCC: ¤head and neck¥ squamous cell carcinoma, R-CHOP: primary rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone therapy, DLBCL: diffuse large B-cell lymphoma, HRPC: hormone-refractory prostate cancer.

141QhK¥ which has been associated with lower BCRP protein expression.52,55¥ Recently, 421ChA was found to greatly affect the stability of BCRP in the endoplasmic reticulum, leading to increased protein degradation via ubiquitination and proteasomal proteolysis.56,57¥ Therefore, 421ChA may lead to increased bioavailability after the oral administration of substrate drugs. Indeed, results of some human studies support this hypothesis; subjects carrying this SNP were found to have elevated plasma concentrations of topotecan,58¥ rosuvastatin,59¥ and sulfasalazine.60¥ Based on the findings in knockout mice, in which the AUC after the oral administration of sulfasalazine was h100 times higher in Bcrp%/% mice than in FVB wild-type mice,61¥ Yamasaki et al.,60¥ tested the contribution of 421ChA to the pharmacokinetic profile of sulfasalazine in healthy subjects. After oral administration, the mean AUC and Cmax was significantly higher, and the mean CLtotal/F was significantly lower in 421A/A than in 421C/C subjects, whereas 421C/A subjects had values between those of the two homozygotes ¤i.e., gene-dose effects¥. The raised AUC of sulfasalazine in subjects with a mutant A allele may be owing to increased oral bioavailability and/or decreased hepatic clearance. Given this, the researchers suggested that ¤1¥ sulfasalazine is a good in vivo probe for BCRP function; and ¤2¥ BCRP works as barrier to restrict the oral absorption and/or biliary excretion of substrate drugs. In contrast to these drugs, no significant differences in pharmacokinetic profiles were recognized for irinotecan,62,63¥ pitavastatin,64¥ or lamivudine.65¥ So, the pharmacogenomic effects of the ABCG2 polymorphisms may depend on the substrate. Since 2005, attention has shifted to small-molecule protein kinase inhibitors and ABCG2 polymorphisms. Imatinib, nilotinib, gefitinib, and erlotinib are reported to be both substrates and inhibitors for BCRP. Cusatis et al.,66¥ who first investigated associations between the 421ChA

variant and diarrhea and skin toxicity in a cohort of 173 Caucasian NSCLC patients receiving oral gefitinib treatment, found that the frequency of diarrhea was significantly higher in patients with at least one 421ChA variant than in patients with the wild-type alleles. In contrast, in Japanese NSCLC patients, no association between 421ChA and 376ChT and susceptibility to gefitinib-induced adverse events ¤diarrhea and other events¥ was recognized.67¥ In another study, a significant association between ¤1143ChT and %15622ChT¥ haplotype and gefitinib-dependent, moderate-to-severe diarrhea was reported.68¥ Two PGx-based studies combined with PK and PD assessments have been conducted for erlotinib and sunitinib. In the erlotinib study, plasma concentrations of erlotinib and its major metabolite, OSI-420, were analyzed using NONMEM software, useful for analyzing population pharmacokinetics, to evaluate the impact of patientsö covariates on erlotinibös pharmacokinetics. The patientsö covariates included SNPs in ABCB1, ABCG2, and CYP3A5. ¤Alanine amino transferase¥ ALAT, age and the ABCG2 polymorphism 421ChA were good predictors for erlotinibös clearance. A significant association between drug exposure and grade of skin rash was also indicated.69¥ Severe adverse events such as hypertension, facial acne and elevation of amylase levels were recognized in one patient, who received 50 mg of sunitinib for renal cell carcinoma, with 2.5-fold higher exposure ¤Cmax and AUC¥ than the other patients. Interestingly, genetic analysis indicated that this patient was homozygous, whereas the remaining patients were wild type or heterozygous, for the 421ChA SNP.70¥ These are a few studies supporting the role of 421ChA based on pharmacokinetic observations. Since BCRP transports purine nucleotide analogues, which resemble the molecular structure of uric acid,71¥ the effect of ABCG2 polymorphisms on serum uric acid levels and subsequently gout is of special interest. Several genome-

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

96

Ichiro IEIRI

wide association studies have been conducted, some indicating that SNPs ¤rs2199936 and 421ChA¥ in the ABCG2 gene showed a significant association with serum urate levels and gout.72,73¥ Dehghan et al. concluded that 421ChA is a causal factor for a 70% increase in gout risk in men compared to women.73¥ Individual genotyping could be useful for clinical decision making, especially for the selection of medications.

8¥

9¥

Conclusion Although many factors, such as diet, age, race and disorders, may influence inter-individual variability in the PK/PD outcomes of pharmacotherapy, the premise that genetic variations in drug-metabolizing enzymes are one of the prime determinants of this variability is strongly supported by numerous human studies. The clinical usefulness of genotyping would be expected to increase if it allowed a more accurate prediction of function or activity in humans. In this regard, the effects of variations of ABC transporter genes on phenotypes ¤i.e., PK/PD profiles and disease states¥ are inconsistent even with the use of the same drugs and in the same ethnic groups. Reasons for these discrepancies remain unclear; however, small sample sizes, substrate specificity, i.e. whether the drugs used really are good substrates for the target transporter, and patientsö backgrounds are all possible factors. Observations based on multicenter trials with large sample sizes and/or metaanalyses are preferable for understanding the impact of the PGx of ABC transporter genes. References 1¥ Ieiri, I., Takane, H. and Otsubo, K.: The MDR1 ¤ABCB1¥ gene polymorphism and its clinical implications. Clin. Pharmacokinet., 43: 553®576 ¤2004¥. 2¥ Ieiri, I., Takane, H., Hirota, T., Otsubo, K. and Higuchi, S.: Genetic polymorphisms of drug transporters: pharmacokinetic and pharmacodynamic consequences in pharmacotherapy. Expert Opin. Drug Metab. Toxicol., 2: 651®674 ¤2006¥. 3¥ Ieiri, I., Higuchi, S. and Sugiyama, Y.: Genetic polymorphisms of uptake ¤OATP1B1, 1B3¥ and efflux ¤MRP2, BCRP¥ transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs. Expert Opin. Drug Metab. Toxicol., 5: 703®729 ¤2009¥. 4¥ Cordon-Cardo, C., OöBrien, J. P., Boccia, J., Casals, D., Bertino, J. R. and Melamed, M. R.: Expression of the multidrug resistance gene product ¤P-glycoprotein¥ in human normal and tumor tissues. J. Histochem. Cytochem., 38: 1277®1287 ¤1990¥. 5¥ Thiebaut, F., Tsuruo, T., Hamada, H., Gottesman, M. M., Pastan, I. and Willingham, M. C.: Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc. Natl. Acad. Sci. USA, 84: 7735®7738 ¤1987¥. 6¥ Borst, P., Schinkel, A. H., Smit, J. J., Wagenaar, E., Van Deemter, L., Smith, A. J., Eijdems, E. W., Baas, F. and Zaman, G. J.: Classical and novel forms of multidrug resistance and the physiological functions of P-glycoprotein in mammals. Pharmacol. Ther., 60: 289®299 ¤1993¥. 7¥ Fojo, A. T., Ueda, K., Slamon, D. J., Poplack, D. G.,

10¥

11¥

12¥

13¥

14¥

15¥

16¥

17¥ 18¥

19¥

20¥

Gottesman, M. M. and Pastan, I.: Expression of a multidrugresistance gene in human tumors and tissues. Proc. Natl. Acad. Sci. USA, 84: 265®269 ¤1987¥. Sugawara, I., Kataoka, I., Morishita, Y., Hamada, H., Tsuruo, T., Itoyama, S. and Mori, S.: Tissue distribution of P-glycoprotein encoded by a multidrug-resistance gene as revealed by a monoclonal antibody, MRK16. Cancer Res., 48: 1926®1929 ¤1988¥. Kim, R. B., Fromm, M. F., Wandel, C., Leake, B., Wood, A. J., Roden, D. M. and Wilkinson, G. R.: The drug transporter Pglycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J. Clin. Invest., 101: 289®294 ¤1998¥. Mayer, U., Wagenaar, E., Beijnen, J. H., Smit, J. W., Meijer, D. K., van Asperen, J., Borst, P. and Schinkel, A. H.: Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by mdr1a Pglycoprotein. Br. J. Pharmacol., 119: 1038®1044 ¤1996¥. Nakamura, Y., Ikeda, S., Furukawa, T., Sumizawa, T., Tani, A., Akiyama, S. and Nagata, Y.: Function of P-glycoprotein expressed in placenta and mole. Biochem. Biophys. Res. Commun., 235: 849® 853 ¤1997¥. Schinkel, A. H., Wagenaar, E., Mol, C. A. and van Deemter, L.: P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Invest., 97: 2517®2524 ¤1996¥. Cordon-Cardo, C., OöBrien, J. P., Casals, D., Rittman-Grauer, L., Biedler, J. L., Melamed, M. R. and Bertino, J. R.: Multidrugresistance gene ¤P-glycoprotein¥ is expressed by endothelial cells at blood-brain barrier sites. Proc. Natl. Acad. Sci. USA, 86: 695®698 ¤1989¥. Schinkel, A. H., Mayer, U., Wagenaar, E., Mol, C. A., van Deemter, L., Smit, J. J., van der Valk, M. A., Voordouw, A. C., Spits, H., van Tellingen, O., Zijlmans, J. M., Fibbe, W. E. and Borst, P.: Normal viability and altered pharmacokinetics in mice lacking mdr1-type ¤drug-transporting¥ P-glycoprotein. Proc. Natl. Acad. Sci. USA, 94: 4028®4033 ¤1997¥. Wacher, V. J., Wu, C. Y. and Benet, L. Z.: Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol. Carcinog., 13: 129®134 ¤1995¥. Kim, R. B., Wandel, C., Leake, B., Cvetkovic, M., Fromm, M. F., Dempsey, P. J., Roden, M. M., Belas, F., Chaudhary, A. K., Roden, D. M., Wood, A. J. and Wilkinson, G. R.: Interrelationship between substrates and inhibitors of human CYP3A and Pglycoprotein. Pharm. Res., 16: 408®414 ¤1999¥. Gottesman, M. M., Hrycyna, C. A., Schoenlein, P. V., Germann, U. A. and Pastan, I.: Genetic analysis of the multidrug transporter. Annu. Rev. Genet., 29: 607®649 ¤1995¥. Mickley, L. A., Lee, J. S., Weng, Z., Zhan, Z., Alvarez, M., Wilson, W., Bates, S. E. and Fojo, T.: Genetic polymorphism in MDR-1: a tool for examining allelic expression in normal cells, unselected and drug-selected cell lines, and human tumors. Blood, 91: 1749®1756 ¤1998¥. Hoffmeyer, S., Burk, O., von Richter, O., Arnold, H. P., Brockmöller, J., Johne, A., Cascorbi, I., Gerloff, T., Roots, I., Eichelbaum, M. and Brinkmann, U.: Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl. Acad. Sci. USA, 97: 3473®3478 ¤2000¥. Tanabe, M., Ieiri, I., Nagata, N., Inoue, K., Ito, S., Kanamori, Y., Takahashi, M., Kurata, Y., Kigawa, J., Higuchi, S., Terakawa, N. and Otsubo, K.: Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance ¤MDR¥-1 gene. J. Pharmacol. Exp. Ther., 297: 1137®1143 ¤2001¥.

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

Human ABCB1 and ABCG2 Gene Polymorphisms

21¥ Ito, S., Ieiri, I., Tanabe, M., Suzuki, A., Higuchi, S. and Otsubo, K.: Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. Pharmacogenetics, 11: 175®184 ¤2001¥. 22¥ Cascorbi, I., Gerloff, T., Johne, A., Meisel, C., Hoffmeyer, S., Schwab, M., Schaeffeler, E., Eichelbaum, M., Brinkmann, U. and Roots, I.: Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin. Pharmacol. Ther., 69: 169®174 ¤2001¥. 23¥ Kim, R. B., Leake, B. F., Choo, E. F., Dresser, G. K., Kubba, S. V., Schwarz, U. I., Taylor, A., Xie, H. G., McKinsey, J., Zhou, S., Lan, L. B., Schuetz, J. D., Schuetz, E. G. and Wilkinson, G. R.: Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin. Pharmacol. Ther., 70: 189®199 ¤2001¥. 24¥ Siegmund, W., Ludwig, K., Giessmann, T., Dazert, P., Schroeder, E., Sperker, B., Warzok, R., Kroemer, H. K. and Cascorbi, I.: The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol. Clin. Pharmacol. Ther., 72: 572®583 ¤2002¥. 25¥ Schwab, M., Eichelbaum, M. and Fromm, M. F.: Genetic polymorphisms of the human MDR1 drug transporter. Annu. Rev. Pharmacol. Toxicol., 43: 285®307 ¤2003¥. 26¥ Sakaeda, T.: MDR1 genotype-related pharmacokinetics: fact or fiction? Drug Metab. Pharmacokinet., 20: 391®414 ¤2005¥. 27¥ Pauli-Magnus, C. and Kroetz, D. L.: Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 ¤ABCB1¥. Pharm. Res., 21: 904®913 ¤2004¥. 28¥ Marzolini, C., Paus, E., Buclin, T. and Kim, R. B.: Polymorphisms in human MDR1 ¤P-glycoprotein¥: recent advances and clinical relevance. Clin. Pharmacol. Ther., 75: 13®33 ¤2004¥. 29¥ Sakaeda, T., Nakamura, T., Horinouchi, M., Kakumoto, M., Ohmoto, N., Sakai, T., Morita, Y., Tamura, T., Aoyama, N., Hirai, M., Kasuga, M. and Okumura, K.: MDR1 genotyperelated pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm. Res., 18: 1400®1404 ¤2001¥. 30¥ Kurata, Y., Ieiri, I., Kimura, M., Morita, T., Irie, S., Urae, A., Ohdo, S., Ohtani, H., Sawada, Y., Higuchi, S. and Otsubo, K.: Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin. Pharmacol. Ther., 72: 209®219 ¤2002¥. 31¥ Jiang, Z. P., Wang, Y. R., Xu, P., Liu, R. R., Zhao, X. L. and Chen, F. P.: Meta-analysis of the effect of MDR1 C3435T polymorphism on cyclosporine pharmacokinetics. Basic Clin. Pharmacol. Toxicol., 103: 433®444 ¤2008¥. 32¥ Gex-Fabry, M., Eap, C. B., Oneda, B., Gervasoni, N., Aubry, J. M., Bondolfi, G. and Bertschy, G.: CYP2D6 and ABCB1 genetic variability: influence on paroxetine plasma level and therapeutic response. Ther. Drug Monit., 30: 474®482 ¤2008¥. 33¥ Nikisch, G., Eap, C. B. and Baumann, P.: Citalopram enantiomers in plasma and cerebrospinal fluid of ABCB1 genotyped depressive patients and clinical response: a pilot study. Psychopharmacology ¤Berl.¥, 181: 751®760 ¤2005¥. 34¥ Fukui, N., Suzuki, Y., Sawamura, K., Sugai, T., Watanabe, J., Inoue, Y. and Someya, T.: Dose-dependent effects of the 3435ChT genotype of ABCB1 gene on the steady-state plasma concentration of fluvoxamine in psychiatric patients. Ther. Drug Monit., 29: 185®189 ¤2007¥. 35¥ Elger, C. E. and Schmidt, D.: Modern management of epilepsy: a practical approach. Epilepsy Behav., 12: 501®539 ¤2008¥. 36¥ Siddiqui, A., Kerb, R., Weale, M. E., Brinkmann, U., Smith, A., Goldstein, D. B., Wood, N. W. and Sisodiya, S. M.: Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N. Engl. J. Med., 348: 1442®1448 ¤2003¥.

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37¥ Haerian, B. S., Roslan, H., Raymond, A. A., Tan, C. T., Lim, K. S., Zulkifli, S. Z., Mohamed, E. H., Tan, H. J. and Mohamed, Z.: ABCB1 C3435T polymorphism and the risk of resistance to antiepileptic drugs in epilepsy: a systematic review and metaanalysis. Seizure, 19: 339®346 ¤2010¥. 38¥ Bournissen, F. G., Moretti, M. E., Juurlink, D. N., Koren, G., Walker, M. and Finkelstein, Y.: Polymorphism of the MDR1/ ABCB1 C3435T drug-transporter and resistance to anticonvulsant drugs: a meta-analysis. Epilepsia, 50: 898®903 ¤2009¥. 39¥ Leschziner, G. D., Andrew, T., Leach, J. P., Chadwick, D., Coffey, A. J., Balding, D. J., Bentley, D. R., Pirmohamed, M. and Johnson, M. R.: Common ABCB1 polymorphisms are not associated with multidrug resistance in epilepsy using a gene-wide tagging approach. Pharmacogenet. Genomics, 17: 217®220 ¤2007¥. 40¥ Marsh, S., Paul, J., King, C. R., Gifford, G., McLeod, H. L. and Brown, R.: Pharmacogenetic assessment of toxicity and outcome after platinum plus taxane chemotherapy in ovarian cancer: the Scottish Randomised Trial in Ovarian Cancer. J. Clin. Oncol., 25: 4528®4535 ¤2007¥. 41¥ Johnatty, S. E., Beesley, J., Paul, J., Fereday, S., Spurdle, A. B., Webb, P. M., Byth, K., Marsh, S. and McLeod, H.: AOCS Study Group: Harnett, P. R., Brown, R., DeFazio, A. and ChenevixTrench, G.: ABCB1 ¤MDR 1¥ polymorphisms and progressionfree survival among women with ovarian cancer following paclitaxel/carboplatin chemotherapy. Clin. Cancer Res., 14: 5594®5601 ¤2008¥. 42¥ Taub, M. E., Mease, K. M., Sane, R. S., Watson, C. A., Chen, L., Ellens, H., Hirakawa, B. P., Reyner, E. L., Jani, M. and Lee, C. A.: Digoxin is not a Substrate for Organic Anion Transporting Polypeptide Transporters OATP1A2, OATP1B1, OATP1B3, and OATP2B1 but is a Substrate for a Sodium Dependent Transporter Expressed in HEK293 Cells. Drug Metab. Dispos., 39: 2093®2102 ¤2011¥. 43¥ Ming, X., Knight, B. M. and Thakker, D. R.: Vectorial Transport of Fexofenadine across Caco-2 Cells: Involvement of Apical Uptake and Basolateral Efflux Transporters. Mol. Pharm., 8: 1677® 1686 ¤2011¥. 44¥ Takano, A., Kusuhara, H., Suhara, T., Ieiri, I., Morimoto, T., Lee, Y. J., Maeda, J., Ikoma, Y., Ito, H., Suzuki, K. and Sugiyama, Y.: Evaluation of in vivo P-glycoprotein function at the blood-brain barrier among MDR1 gene polymorphisms by using 11C-verapamil. J. Nucl. Med., 47: 1427®1433 ¤2006¥. 45¥ Brunner, M., Langer, O., Sunder-Plassmann, R., Dobrozemsky, G., Müller, U., Wadsak, W., Krcal, A., Karch, R., Mannhalter, C., Dudczak, R., Kletter, K., Steiner, I., Baumgartner, C. and Müller, M.: Influence of functional haplotypes in the drug transporter gene ABCB1 on central nervous system drug distribution in humans. Clin. Pharmacol. Ther., 78: 182®190 ¤2005¥. 46¥ Doyle, L. A., Yang, W., Abruzzo, L. V., Krogmann, T., Gao, Y., Rishi, A. K. and Ross, D. D.: A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc. Natl. Acad. Sci. USA, 95: 15665®15670 ¤1998¥. 47¥ Staud, F. and Pavek, P.: Breast cancer resistance protein ¤BCRP/ ABCG2¥. Int. J. Biochem. Cell Biol., 37: 720®725 ¤2005¥. 48¥ Xu, J., Liu, Y., Yang, Y., Bates, S. and Zhang, J. T.: Characterization of oligomeric human half-ABC transporter ATP-binding cassette G2. J. Biol. Chem., 279: 19781®19789 ¤2004¥. 49¥ Kage, K., Tsukahara, S., Sugiyama, T., Asada, S., Ishikawa, E., Tsuruo, T. and Sugimoto, Y.: Dominant-negative inhibition of breast cancer resistance protein as drug efflux pump through the inhibition of S-S dependent homodimerization. Int. J. Cancer, 97: 626®630 ¤2002¥. 50¥ Iida, A., Saito, S., Sekine, A., Mishima, C., Kitamura, Y.,

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Kondo, K., Harigae, S., Osawa, S. and Nakamura, Y.: Catalog of 605 single-nucleotide polymorphisms ¤SNPs¥ among 13 genes encoding human ATP-binding cassette transporters: ABCA4, ABCA7, ABCA8, ABCD1, ABCD3, ABCD4, ABCE1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5, and ABCG8. J. Hum. Genet., 47: 285®310 ¤2002¥. Zamber, C. P., Lamba, J. K., Yasuda, K., Farnum, J., Thummel, K., Schuetz, J. D. and Schuetz, E. G.: Natural allelic variants of breast cancer resistance protein ¤BCRP¥ and their relationship to BCRP expression in human intestine. Pharmacogenetics, 13: 19®28 ¤2003¥. Kobayashi, D., Ieiri, I., Hirota, T., Takane, H., Maegawa, S., Kigawa, J., Suzuki, H., Nanba, E., Oshimura, M., Terakawa, N., Otsubo, K., Mine, K. and Sugiyama, Y.: Functional assessment of ABCG2 ¤BCRP¥ gene polymorphisms to protein expression in human placenta. Drug Metab. Dispos., 33: 94®101 ¤2005¥. Bäckström, G., Taipalensuu, J., Melhus, H., Brändström, H., Svensson, A. C., Artursson, P. and Kindmark, A.: Genetic variation in the ATP-binding cassette transporter gene ABCG2 ¤BCRP¥ in a Swedish population. Eur. J. Pharm. Sci., 18: 359®364 ¤2003¥. Sparreboom, A., Gelderblom, H., Marsh, S., Ahluwalia, R., Obach, R., Principe, P., Twelves, C., Verweij, J. and McLeod, H. L.: Diflomotecan pharmacokinetics in relation to ABCG2 421ChA genotype. Clin. Pharmacol. Ther., 76: 38®44 ¤2004¥. Kondo, C., Suzuki, H., Itoda, M., Ozawa, S., Sawada, J., Kobayashi, D., Ieiri, I., Mine, K., Ohtsubo, K. and Sugiyama, Y.: Functional analysis of SNPs variants of BCRP/ABCG2. Pharm. Res., 21: 1895®1903 ¤2004¥. Nakagawa, H., Tamura, A., Wakabayashi, K., Hoshijima, K., Komada, M., Yoshida, T., Kometani, S., Matsubara, T., Mikuriya, K. and Ishikawa, T.: Ubiquitin-mediated proteasomal degradation of non-synonymous SNP variants of human ABC transporter ABCG2. Biochem. J., 411: 623®631 ¤2008¥. Furukawa, T., Wakabayashi, K., Tamura, A., Nakagawa, H., Morishima, Y., Osawa, Y. and Ishikawa, T.: Major SNP ¤Q141K¥ variant of human ABC transporter ABCG2 undergoes lysosomal and proteasomal degradations. Pharm. Res., 26: 469®479 ¤2009¥. Sparreboom, A., Loos, W. J., Burger, H., Sissung, T. M., Verweij, J., Figg, W. D., Nooter, K. and Gelderblom, H.: Effect of ABCG2 genotype on the oral bioavailability of topotecan. Cancer Biol. Ther., 4: 650®653 ¤2005¥. Zhang, W., Yu, B. N., He, Y. J., Fan, L., Li, Q., Liu, Z. Q., Wang, A., Liu, Y. L., Tan, Z. R., Fen-Jiang, Huang, Y. F. and Zhou, H. H.: Role of BCRP 421ChA polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males. Clin. Chim. Acta, 373: 99®103 ¤2006¥. Yamasaki, Y., Ieiri, I., Kusuhara, H., Sasaki, T., Kimura, M., Tabuchi, H., Ando, Y., Irie, S., Ware, J., Nakai, Y., Higuchi, S. and Sugiyama, Y.: Pharmacogenetic characterization of sulfasalazine disposition based on NAT2 and ABCG2 ¤BCRP¥ gene polymorphisms in humans. Clin. Pharmacol. Ther., 84: 95®103 ¤2008¥. Zaher, H., Khan, A. A., Palandra, J., Brayman, T. G., Yu, L. and Ware, J. A.: Breast cancer resistance protein ¤Bcrp/abcg2¥ is a major determinant of sulfasalazine absorption and elimination in the mouse. Mol. Pharm., 3: 55®61 ¤2006¥. Han, J. Y., Lim, H. S., Yoo, Y. K., Shin, E. S., Park, Y. H., Lee, S. Y., Lee, J. E., Lee, D. H., Kim, H. T. and Lee, J. S.: Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer. Cancer, 110: 138®147 ¤2007¥. de Jong, F. A., Marsh, S., Mathijssen, R. H., King, C., Verweij, J., Sparreboom, A. and McLeod, H. L.: ABCG2 pharmaco-

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genetics: ethnic differences in allele frequency and assessment of influence on irinotecan disposition. Clin. Cancer Res., 10: 5889® 5894 ¤2004¥. Ieiri, I., Suwannakul, S., Maeda, K., Uchimaru, H., Hashimoto, K., Kimura, M., Fujino, H., Hirano, M., Kusuhara, H., Irie, S., Higuchi, S. and Sugiyama, Y.: SLCO1B1 ¤OATP1B1, an uptake transporter¥ and ABCG2 ¤BCRP, an efflux transporter¥ variant alleles and pharmacokinetics of pitavastatin in healthy volunteers. Clin. Pharmacol. Ther., 82: 541®547 ¤2007¥. Zamboni, W. C., Ramanathan, R. K., McLeod, H. L., Mani, S., Potter, D. M., Strychor, S., Maruca, L. J., King, C. R., Jung, L. L., Parise, R. A., Egorin, M. J., Davis, T. A. and Marsh, S.: Disposition of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite in relation to ABC transporter genotypes. Invest. New Drugs, 24: 393®401 ¤2006¥. Cusatis, G., Gregorc, V., Li, J., Spreafico, A., Ingersoll, R. G., Verweij, J., Ludovini, V., Villa, E. and Hidalgo, M.: Pharmacogenetics of ABCG2 and adverse reactions to gefitinib. J. Natl. Cancer Inst., 98: 1739®1742 ¤2006¥. Akasaka, K., Kaburagi, T., Yasuda, S., Ohmori, K., Abe, K., Sagara, H., Ueda, Y., Nagao, K., Imura, J. and Imai, Y.: Impact of functional ABCG2 polymorphisms on the adverse effects of gefitinib in Japanese patients with non-small-cell lung cancer. Cancer Chemother. Pharmacol., 66: 691®698 ¤2010¥. Lemos, C., Giovannetti, E., Zucali, P. A., Assaraf, Y. G., Scheffer, G. L., van der Straaten, T., DöIncecco, A., Falcone, A., Guchelaar, H. J., Danesi, R., Santoro, A., Giaccone, G., Tibaldi, C. and Peters, G. J.: Impact of ABCG2 polymorphisms on the clinical outcome and toxicity of gefitinib in non-small-cell lung cancer patients. Pharmacogenomics, 12: 159®170 ¤2011¥. Thomas, F., Rochaix, P., White-Koning, M., Hennebelle, I., Sarini, J., Benlyazid, A., Malard, L., Lefebvre, J. L., Chatelut, E. and Delord, J. P.: Population pharmacokinetics of erlotinib and its pharmacokinetic/pharmacodynamic relationships in head and neck squamous cell carcinoma. Eur. J. Cancer, 45: 2316®2323 ¤2009¥. Mizuno, T., Terada, T., Kamba, T., Fukudo, M., Katsura, T., Nakamura, E., Ogawa, O. and Inui, K.: ABCG2 421ChA polymorphism and high exposure of sunitinib in a patient with renal cell carcinoma. Ann. Oncol., 21: 1382®1383 ¤2010¥. Takenaka, K., Morgan, J. A., Scheffer, G. L., Adachi, M., Stewart, C. F., Sun, D., Leggas, M., Ejendal, K. F., Hrycyna, C. A. and Schuetz, J. D.: Substrate overlap between Mrp4 and Abcg2/Bcrp affects purine analogue drug cytotoxicity and tissue distribution. Cancer Res., 67: 6965®6972 ¤2007¥. Yang, Q., Köttgen, A., Dehghan, A., Smith, A. V., Glazer, N. L., Chen, M. H., Chasman, D. I., Aspelund, T., Eiriksdottir, G., Harris, T. B., Launer, L., Nalls, M., Hernandez, D., Arking, D. E., Boerwinkle, E., Grove, M. L., Li, M., Linda Kao, W. H., Chonchol, M., Haritunians, T., Li, G., Lumley, T., Psaty, B. M., Shlipak, M., Hwang, S. J., Larson, M. G., OöDonnell, C. J., Upadhyay, A., van Duijn, C. M., Hofman, A., Rivadeneira, F., Stricker, B., Uitterlinden, A. G., Paré, G., Parker, A. N., Ridker, P. M., Siscovick, D. S., Gudnason, V., Witteman, J. C., Fox, C. S. and Coresh, J.: Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circ. Cardiovasc. Genet., 3: 523®530 ¤2010¥. Dehghan, A., Köttgen, A., Yang, Q., Hwang, S. J., Kao, W. L., Rivadeneira, F., Boerwinkle, E., Levy, D., Hofman, A., Astor, B. C., Benjamin, E. J., van Duijn, C. M., Witteman, J. C., Coresh, J. and Fox, C. S.: Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet, 372: 1953®1961 ¤2008¥. Jafar, T., Prasad, N., Agarwal, V., Mahdi, A., Gupta, A., Sharma, R. K., Negi, M. and Agrawal, S.: MDR-1 gene polymorphisms in steroid-responsive versus steroid-resistant

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nephrotic syndrome in children. Nephrol. Dial. Transplant., 26: 3968®3974 ¤2011¥. Dong, L., Luo, R., Tong, Y., Cai, X., Mao, M. and Yu, D.: Lack of association between ABCB1 gene polymorphisms and pharmacoresistant epilepsy: an analysis in a western Chinese pediatric population. Brain Res., 1391: 114®124 ¤2011¥. Hoenig, M. R., Walker, P. J., Gurnsey, C., Beadle, K. and Johnson, L.: The C3435T polymorphism in ABCB1 influences atorvastatin efficacy and muscle symptoms in a high-risk vascular cohort. J. Clin. Lipidol., 5: 91®96 ¤2011¥. Haerian, B. S., Lim, K. S., Tan, H. J., Mohamed, E. H., Tan, C. T., Raymond, A. A., Wong, C. P., Wong, S. W., Omar, H., Roslan, H. and Mohamed, Z.: Association between ABCB1 polymorphism and response to sodium valproate treatment in Malaysian epilepsy patients. Epileptic Disord., 13: 65®75 ¤2011¥. Zwisler, S. T., Enggaard, T. P., Mikkelsen, S., Verstuyft, C., Becquemont, L., Sindrup, S. H. and Brosen, K.: Lack of Association of OPRM1 and ABCB1 Single-Nucleotide Polymorphisms to Oxycodone Response in Postoperative Pain. J. Clin. Pharmacol., ¤2011¥ ªEpub ahead of print«. Narumiya, K., Metzger, R., Bollschweiler, E., Alakus, H., Brabender, J., Drebber, U., Hölscher, A. H. and WarneckeEberz, U.: Impact of ABCB1 C3435T polymorphism on lymph node regression in multimodality treatment of locally advanced esophageal cancer. Pharmacogenomics, 12: 205®214 ¤2011¥. Saricaoglu, H., Yilmaz, M., Karkucak, M., Ozturk, H. Z., Yakut, T., Gulten, T., Baskan, E. B., Aydogan, K. and Dilek, K.: Investigation of ABCB1 gene polymorphism with colchicine response in Behçetös disease. Genet. Mol. Res., 10: 1®6 ¤2011¥. Obermann-Borst, S. A., Isaacs, A., Younes, Z., van Schaik, R. H., van der Heiden, I. P., van Duyn, C. M., Steegers, E. A. and Steegers-Theunissen, R. P.: General maternal medication use, folic acid, the MDR1 C3435T polymorphism, and the risk of a child with a congenital heart defect. Am. J. Obstet. Gynecol., 204: 236.e1®236.e8 ¤2011¥. Gonzalez-Haba, E., García, M. I., Cortejoso, L., López-Lillo, C., Barrueco, N., García-Alfonso, P., Alvarez, S., Jiménez, J. L., Martín, M. L., Muñóz-Fernández, M. A., Sanjurjo, M. and López-Fernández, L. A.: ABCB1 gene polymorphisms are associated with adverse reactions in fluoropyrimidine-treated colorectal cancer patients. Pharmacogenomics, 11: 1715®1723 ¤2010¥. Rao, D. N., Anuradha, C., Vishnupriya, S., Sailaja, K., Surekha, D., Raghunadharao, D. and Rajappa, S.: Association of an MDR1 gene ¤C3435T¥ polymorphism with acute leukemia in India. Asian Pac. J. Cancer Prev., 11: 1063®1066 ¤2010¥. Parkman, H. P., Jacobs, M. R., Mishra, A., Hurdle, J. A., Sachdeva, P., Gaughan, J. P. and Krynetskiy, E.: Domperidone treatment for gastroparesis: demographic and pharmacogenetic characterization of clinical efficacy and side-effects. Dig. Dis. Sci., 56: 115®124 ¤2011¥. Fransson, M. N., Gréen, H., Litton, J. E. and Friberg, L. E.: Influence of Cremophor EL and genetic polymorphisms on the pharmacokinetics of paclitaxel and its metabolites using a mechanism-based model. Drug Metab. Dispos., 39: 247®255 ¤2011¥. Herrero, M. J., Almenar, L., Jordán, C., Sánchez, I., Poveda, J. L. and Aliño, S. F.: Clinical interest of pharmacogenetic polymorphisms in the immunosuppressive treatment after heart transplantation. Transplant. Proc., 42: 3181®3182 ¤2010¥. Grimm, C., Polterauer, S., Zeillinger, R., Tong, D., Heinze, G., Wolf, A., Natter, C., Reinthaller, A. and Hefler, L. A.: Two multidrug-resistance ¤ABCB1¥ gene polymorphisms as prognostic parameters in women with ovarian cancer. Anticancer Res., 30: 3487®3491 ¤2010¥.

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88¥ Elens, L., Vandercam, B., Yombi, J. C., Lison, D., Wallemacq, P. and Haufroid, V.: Influence of host genetic factors on efavirenz plasma and intracellular pharmacokinetics in HIV-1-infected patients. Pharmacogenomics, 11: 1223®1234 ¤2010¥. 89¥ Shitara, K., Matsuo, K., Ito, S., Sawaki, A., Kawai, H., Yokota, T., Takahari, D., Shibata, T., Ura, T., Ito, H., Hosono, S., Kawase, T., Watanabe, M., Tajima, K., Yatabe, Y., Tanaka, H. and Muro, K.: Effects of genetic polymorphisms in the ABCB1 gene on clinical outcomes in patients with gastric cancer treated by second-line chemotherapy. Asian Pac. J. Cancer Prev., 11: 447®452 ¤2010¥. 90¥ Wallentin, L., James, S., Storey, R. F., Armstrong, M., Barratt, B. J., Horrow, J., Husted, S., Katus, H., Steg, P. G., Shah, S. H. and Becker, R. C.: PLATO investigators: Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet, 376: 1320®1328 ¤2010¥. 91¥ Mega, J. L., Close, S. L., Wiviott, S. D., Shen, L., Walker, J. R., Simon, T., Antman, E. M., Braunwald, E. and Sabatine, M. S.: Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet, 376: 1312®1319 ¤2010¥. 92¥ Choi, E. M., Lee, M. G., Lee, S. H., Choi, K. W. and Choi, S. H.: Association of ABCB1 polymorphisms with the efficacy of ondansetron for postoperative nausea and vomiting. Anaesthesia, 65: 996®1000 ¤2010¥. 93¥ Menu, P., Gressier, F., Verstuyft, C., Hardy, P., Becquemont, L. and Corruble, E.: Antidepressants and ABCB1 gene C3435T functional polymorphism: a naturalistic study. Neuropsychobiology, 62: 193®197 ¤2010¥. 94¥ Fajac, A., Gligorov, J., Rezai, K., Lévy, P., Lévy, E., Selle, F., Beerblock, K., Avenin, D., Saintigny, P., Hugonin, S., Bernaudin, J. F. and Lokiec, F.: Effect of ABCB1 C3435T polymorphism on docetaxel pharmacokinetics according to menopausal status in breast cancer patients. Br. J. Cancer, 103: 560®566 ¤2010¥. 95¥ Sia, A. T., Sng, B. L., Lim, E. C., Law, H. and Tan, E. C.: The influence of ATP-binding cassette sub-family B member-1 ¤ABCB1¥ genetic polymorphisms on acute and chronic pain after intrathecal morphine for caesarean section: a prospective cohort study. Int. J. Obstet. Anesth., 19: 254®260 ¤2010¥. 96¥ Lu, P. H., Wei, M. X., Yang, J., Liu, X., Tao, G. Q., Shen, W. and Chen, M. B.: Association between two polymorphisms of ABCB1 and breast cancer risk in the current studies: a metaanalysis. Breast Cancer Res. Treat., 125: 537®543 ¤2011¥. 97¥ Jovanović, N., Božina, N., Lovrić, M., Medved, V., Jakovljević, M. and Peleš, A. M.: The role of CYP2D6 and ABCB1 pharmacogenetics in drug-naïve patients with first-episode schizophrenia treated with risperidone. Eur. J. Clin. Pharmacol., 66: 1109®1117 ¤2010¥. 98¥ Dutheil, F., Beaune, P., Tzourio, C., Loriot, M. A. and Elbaz, A.: Interaction between ABCB1 and professional exposure to organochlorine insecticides in Parkinson disease. Arch. Neurol., 67: 739®745 ¤2010¥. 99¥ Sarginson, J. E., Lazzeroni, L. C., Ryan, H. S., Ershoff, B. D., Schatzberg, A. F. and Murphy, G. M., Jr.: ABCB1 ¤MDR1¥ polymorphisms and antidepressant response in geriatric depression. Pharmacogenet. Genomics, 20: 467®475 ¤2010¥. 100¥ Balcerczak, E., Panczyk, M., Piaskowski, S., Pasz-Walczak, G., Sałagacka, A. and Mirowski, M.: ABCB1/MDR1 gene polymorphisms as a prognostic factor in colorectal cancer. Int. J. Colorectal Dis., 25: 1167®1176 ¤2010¥. 101¥ Buda, G., Ricci, D., Huang, C. C., Favis, R., Cohen, N.,

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Zhuang, S. H., Harousseau, J. L., Sonneveld, P., Bladé, J. and Orlowski, R. Z.: Polymorphisms in the multiple drug resistance protein 1 and in P-glycoprotein 1 are associated with time to event outcomes in patients with advanced multiple myeloma treated with bortezomib and pegylated liposomal doxorubicin. Ann. Hematol., 89: 1133®1140 ¤2010¥. Woillard, J. B., Rerolle, J. P., Picard, N., Rousseau, A., Guillaudeau, A., Munteanu, E., Essig, M., Drouet, M., Le Meur, Y. and Marquet, P.: Donor P-gp polymorphisms strongly influence renal function and graft loss in a cohort of renal transplant recipients on cyclosporine therapy in a long-term follow-up. Clin. Pharmacol. Ther., 88: 95®100 ¤2010¥. Park, W. B., Choe, P. G., Song, K. H., Jeon, J. H., Park, S. W., Kim, H. B., Kim, N. J., Oh, M. D. and Choe, K. W.: Genetic factors influencing severe atazanavir-associated hyperbilirubinemia in a population with low UDP-glucuronosyltransferase 1A1*28 allele frequency. Clin. Infect. Dis., 51: 101®106 ¤2010¥. Cho, H. Y., Yoo, H. D. and Lee, Y. B.: Influence of ABCB1 genetic polymorphisms on the pharmacokinetics of levosulpiride in healthy subjects. Neuroscience, 169: 378®387 ¤2010¥. Xiang, Q., Zhao, X., Zhou, Y., Duan, J. L. and Cui, Y. M.: Effect of CYP2D6, CYP3A5, and MDR1 genetic polymorphisms on the pharmacokinetics of risperidone and its active moiety. J. Clin. Pharmacol., 50: 659®666 ¤2010¥. Ni, L. N., Li, J. Y., Miao, K. R., Qiao, C., Zhang, S. J., Qiu, H. R. and Qian, S. X.: Multidrug resistance gene ¤MDR1¥ polymorphisms correlate with imatinib response in chronic myeloid leukemia. Med. Oncol., 28: 265®269 ¤2011¥. McCracken, J. T., Aman, M. G., McDougle, C. J., Tierney, E., Shiraga, S., Whelan, F., Arnold, L. E., Posey, D., Ritz, L., Vitiello, B. and Scahill, L.: Possible influence of variant of the P-glycoprotein gene ¤MDR1/ABCB1¥ on clinical response to guanfacine in children with pervasive developmental disorders and hyperactivity. J. Child Adolesc. Psychopharmacol., 20: 1®5 ¤2010¥. Choi, B. S., Alberti, D. B., Schelman, W. R., Kolesar, J. M., Thomas, J. P., Marnocha, R., Eickhoff, J. C., Ivy, S. P., Wilding, G. and Holen, K. D.: The maximum tolerated dose and biologic effects of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone ¤3-AP¥ in combination with irinotecan for patients with refractory solid tumors. Cancer Chemother. Pharmacol., 66: 973®980 ¤2010¥. Bellusci, C. P., Rocco, C. A., Aulicino, P. C., Mecikovsky, D., Bologna, R., Sen, L. and Mangano, A.: MDR1 3435T and 1236T alleles delay disease progression to pediatric AIDS but have no effect on HIV-1 vertical transmission. AIDS, 24: 833®840 ¤2010¥. Cho, H. Y., Yoon, H., Park, G. K. and Lee, Y. B.: Pharmacokinetics and bioequivalence of two formulations of rebamipide 100-mg tablets: a randomized, single-dose, twoperiod, two-sequence crossover study in healthy Korean male volunteers. Clin. Ther., 31: 2712®2721 ¤2009¥. Sánchez, M. B., Herranz, J. L., Leno, C., Arteaga, R., Oterino, A., Valdizán, E. M., Nicolás, J. M., Adín, J. and Armijo, J. A.: Genetic factors associated with drug-resistance of epilepsy: relevance of stratification by patient age and aetiology of epilepsy. Seizure, 19: 93®101 ¤2010¥. Taegtmeyer, A. B., Breen, J. B., Smith, J., Burke, M., Leaver, N., Pantelidis, P., Lyster, H., Yacoub, M. H., Barton, P. J. and Banner, N. R.: ATP-binding cassette subfamily B member 1 polymorphisms do not determine cyclosporin exposure, acute rejection or nephrotoxicity after heart transplantation. Transplantation, 89: 75®82 ¤2010¥. Kastelic, M., Koprivsek, J., Plesnicar, B. K., Serretti, A., Mandelli, L., Locatelli, I., Grabnar, I. and Dolzan, V.: MDR1 gene polymorphisms and response to acute risperidone treatment. Prog. Neuropsychopharmacol. Biol. Psychiatry, 34: 387®392 ¤2010¥. Ciccacci, C., Borgiani, P., Ceffa, S., Sirianni, E., Marazzi, M. C.,

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Altan, A. M., Paturzo, G., Bramanti, P., Novelli, G. and Palombi, L.: Nevirapine-induced hepatotoxicity and pharmacogenetics: a retrospective study in a population from Mozambique. Pharmacogenomics, 11: 23®31 ¤2010¥. Chang, H., Rha, S. Y., Jeung, H. C., Im, C. K., Noh, S. H., Kim, J. J. and Chung, H. C.: Association of the ABCB1 3435ChT polymorphism and treatment outcomes in advanced gastric cancer patients treated with paclitaxel-based chemotherapy. Oncol. Rep., 23: 271®278 ¤2010¥. Andersen, V., Ostergaard, M., Christensen, J., Overvad, K., Tjønneland, A. and Vogel, U.: Polymorphisms in the xenobiotic transporter Multidrug Resistance 1 ¤MDR1¥ and interaction with meat intake in relation to risk of colorectal cancer in a Danish prospective case-cohort study. BMC Cancer, 9: 407 ¤2009¥. He, X. J., Zhao, L. M., Qiu, F., Sun, Y. X. and Li-Ling, J.: Influence of ABCB1 gene polymorphisms on the pharmacokinetics of azithromycin among healthy Chinese Han ethnic subjects. Pharmacol. Rep., 61: 843®850 ¤2009¥. Becker, M. L., Visser, L. E., van Schaik, R. H., Hofman, A., Uitterlinden, A. G. and Stricker, B. H.: Common genetic variation in the ABCB1 gene is associated with the cholesterollowering effect of simvastatin in males. Pharmacogenomics, 10: 1743®1751 ¤2009¥. Paule, B., Castagne, V., Picard, V., Saffroy, R., Adam, R., Guettier, C., Farinotti, R. and Bonhomme-Faivre, L.: MDR1 polymorphism role in patients treated with cetuximab and irinotecan in irinotecan refractory colorectal cancer. Med. Oncol., 27: 1066®1072 ¤2010¥. Zwisler, S. T., Enggaard, T. P., Noehr-Jensen, L., Mikkelsen, S., Verstuyft, C., Becquemont, L., Sindrup, S. H. and Brosen, K.: The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes. Fundam. Clin. Pharmacol., 24: 517®524 ¤2010¥. Droździk, M., Stefankiewicz, J., Kurzawa, R., Górnik, W., Baczkowski, T. and Kurzawski, M.: Association of the MDR1 ¤ABCB1¥ gene 3435ChT polymorphism with male infertility. Pharmacol. Rep., 61: 690®696 ¤2009¥. Bliek, B. J., van Schaik, R. H., van der Heiden, I. P., SayedTabatabaei, F. A., van Duijn, C. M., Steegers, E. A. and SteegersTheunissen, R. P.: Eurocran Gene-Environment Interaction Group: Maternal medication use, carriership of the ABCB1 3435C h T polymorphism and the risk of a child with cleft lip with or without cleft palate. Am. J. Med. Genet. A., 149A: 2088® 2092 ¤2009¥. Hawwa, A. F., McKiernan, P. J., Shields, M., Millership, J. S., Collier, P. S. and McElnay, J. C.: Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant. Br. J. Clin. Pharmacol., 68: 413®421 ¤2009¥. Zhao, L. M., He, X. J., Qiu, F., Sun, Y. X. and Li-Ling, J.: Influence of ABCB1 gene polymorphisms on the pharmacokinetics of verapamil among healthy Chinese Han ethnic subjects. Br. J. Clin. Pharmacol., 68: 395®401 ¤2009¥. Bonhomme-Faivre, L., Picard, V., Saliba, F., Abbara, C., Fodil, M., Chaunoy, M. and Farinotti, R.: Effect of the ABCB1 3435ChT polymorphism on tacrolimus concentrations and dosage requirements in liver transplant recipients. Am. J. Health Syst. Pharm., 66: 1645®1651 ¤2009¥. Keskitalo, J. E., Kurkinen, K. J., Neuvonen, M., Backman, J. T., Neuvonen, P. J. and Niemi, M.: No significant effect of ABCB1 haplotypes on the pharmacokinetics of fluvastatin, pravastatin, lovastatin, and rosuvastatin. Br. J. Clin. Pharmacol., 68: 207®213 ¤2009¥. van Erp, N. P., Eechoute, K., van der Veldt, A. A., Haanen,

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

Human ABCB1 and ABCG2 Gene Polymorphisms

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J. B., Reyners, A. K., Mathijssen, R. H., Boven, E., van der Straaten, T., Baak-Pablo, R. F., Wessels, J. A., Guchelaar, H. J. and Gelderblom, H.: Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. J. Clin. Oncol., 27: 4406®4412 ¤2009¥. Consoli, G., Lastella, M., Ciapparelli, A., Catena DellöOsso, M., Ciofi, L., Guidotti, E., Danesi, R., DellöOsso, L., Del Tacca, M. and Di Paolo, A.: ABCB1 polymorphisms are associated with clozapine plasma levels in psychotic patients. Pharmacogenomics, 10: 1267®1276 ¤2009¥. George, J., Dharanipragada, K., Krishnamachari, S., Chandrasekaran, A., Sam, S. S. and Sunder, E.: A singlenucleotide polymorphism in the MDR1 gene as a predictor of response to neoadjuvant chemotherapy in breast cancer. Clin. Breast Cancer, 9: 161®165 ¤2009¥. Benyamina, A., Bonhomme-Faivre, L., Picard, V., Sabbagh, A., Richard, D., Blecha, L., Rahioui, H., Karila, L., Lukasiewicz, M., Farinotti, R., Picard, V., Marill, C. and Reynaud, M.: Association between ABCB1 C3435T polymorphism and increased risk of cannabis dependence. Prog. Neuropsychopharmacol. Biol. Psychiatry, 33: 1270®1274 ¤2009¥. Yin, O. Q., Tomlinson, B. and Chow, M. S.: Effect of multidrug resistance gene-1 ¤ABCB1¥ polymorphisms on the single-dose pharmacokinetics of cloxacillin in healthy adult Chinese men. Clin. Ther., 31: 999®1006 ¤2009¥. Panczyk, M., Balcerczak, E., Piaskowski, S., Jamroziak, K., PaszWalczak, G. and Mirowski, M.: ABCB1 gene polymorphisms and haplotype analysis in colorectal cancer. Int. J. Colorectal Dis., 24: 895®905 ¤2009¥. Drain, S., Catherwood, M. A., Orr, N., Galligan, L., Rea, I. M., Hodkinson, C., Drake, M. B., Kettle, P. J., Morris, T. C. and Alexander, H. D.: ABCB1 ¤MDR1¥ rs1045642 is associated with increased overall survival in plasma cell myeloma. Leuk. Lymphoma, 50: 566®570 ¤2009¥. Lara, P. N., Jr., Natale, R., Crowley, J., Lenz, H. J., Redman, M. W., Carleton, J. E., Jett, J., Langer, C. J., Kuebler, J. P., Dakhil, S. R., Chansky, K. and Gandara, D. R.: Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J. Clin. Oncol., 27: 2530®2535 ¤2009¥. Tahara, T., Shibata, T., Nakamura, M., Yamashita, H., Yoshioka, D., Okubo, M., Maruyama, N., Kamano, T., Kamiya, Y., Nakagawa, Y., Fujita, H., Nagasaka, M., Iwata, M., Takahama, K., Watanabe, M., Hirata, I. and Arisawa, T.: Effect of MDR1 gene promoter methylation in patients with ulcerative colitis. Int. J. Mol. Med., 23: 521®527 ¤2009¥. Hosohata, K., Masuda, S., Yonezawa, A., Katsura, T., Oike, F., Ogura, Y., Takada, Y., Egawa, H., Uemoto, S. and Inui, K.: MDR1 haplotypes conferring an increased expression of intestinal CYP3A4 rather than MDR1 in female living-donor liver transplant patients. Pharm. Res., 26: 1590®1595 ¤2009¥. Kodaira, C., Sugimoto, M., Nishino, M., Yamade, M., Shirai, N., Uchida, S., Ikuma, M., Yamada, S., Watanabe, H., Hishida, A. and Furuta, T.: Effect of MDR1 C3435T polymorphism on lansoprazole in healthy Japanese subjects. Eur. J. Clin. Pharmacol., 65: 593®600 ¤2009¥. Estrela, R. C., Ribeiro, F. S., Barroso, P. F., Tuyama, M., Gregório, S. P., Dias-Neto, E., Struchiner, C. J. and SuarezKurtz, G.: ABCB1 polymorphisms and the concentrations of lopinavir and ritonavir in blood, semen and saliva of HIV-infected men under antiretroviral therapy. Pharmacogenomics, 10: 311®318 ¤2009¥. Westerlund, M., Belin, A. C., Anvret, A., Håkansson, A., Nissbrandt, H., Lind, C., Sydow, O., Olson, L. and Galter, D.: Association of a polymorphism in the ABCB1 gene with

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Parkinsonös disease. Parkinsonism Relat. Disord., 15: 422®424 ¤2009¥. Ashariati, A.: Polymorphism C3435T of the MDR-1 gene predict response to preoperative chemotherapy in locally advanced breast cancer with Her2/neu expression. Acta Med. Indones., 40: 187®191 ¤2008¥. Krupoves, A., Seidman, E. G., Mack, D., Israel, D., Morgan, K., Lambrette, P., Costea, I., Deslandres, C., Grimard, G., Law, L., Levy, E. and Amre, D. K.: Associations between ABCB1/MDR1 gene polymorphisms and Crohnös disease: a gene-wide study in a pediatric population. Inflamm. Bowel Dis., 15: 900®908 ¤2009¥. Guo, X., Chen, X. P., Cheng, Z. N., Luo, X., Guo, R., Chen, L., Chen, J., Chen, B., Peng, J. and Li, Y. J.: No effect of MDR1 C3435T polymorphism on oral pharmacokinetics of telmisartan in 19 healthy Chinese male subjects. Clin. Chem. Lab. Med., 47: 38®43 ¤2009¥. Curras, V., Hocht, C., Mangano, A., Niselman, V., Mariño Hernández, E., Cáceres Guido, P., Mecikovsky, D., Bellusci, C., Bologna, R., Sen, L., Rubio, M. C. and Bramuglia, G. F.: Pharmacokinetic study of the variability of indinavir drug levels when boosted with ritonavir in HIV-infected children. Pharmacology, 83: 59®66 ¤2009¥. Weiss, J., Ten Hoevel, M. M., Burhenne, J., Walter-Sack, I., Hoffmann, M. M., Rengelshausen, J., Haefeli, W. E. and Mikus, G.: CYP2C19 genotype is a major factor contributing to the highly variable pharmacokinetics of voriconazole. J. Clin. Pharmacol., 49: 196®204 ¤2009¥. Juyal, G., Midha, V., Amre, D., Sood, A., Seidman, E. and Thelma, B. K.: Associations between common variants in the MDR1 ¤ABCB1¥ gene and ulcerative colitis among North Indians. Pharmacogenet. Genomics, 19: 77®85 ¤2009¥. Bandur, S., Petrasek, J., Hribova, P., Novotna, E., Brabcova, I. and Viklicky, O.: Haplotypic structure of ABCB1/MDR1 gene modifies the risk of the acute allograft rejection in renal transplant recipients. Transplantation, 86: 1206®1213 ¤2008¥. Wang, Y., Wang, C., Li, J., Wang, X., Zhu, G., Chen, X., Bi, H. and Huang, M.: Effect of genetic polymorphisms of CYP3A5 and MDR1 on cyclosporine concentration during the early stage after renal transplantation in Chinese patients co-treated with diltiazem. Eur. J. Clin. Pharmacol., 65: 239®247 ¤2009¥. Chang, H., Rha, S. Y., Jeung, H. C., Im, C. K., Ahn, J. B., Kwon, W. S., Yoo, N. C., Roh, J. K. and Chung, H. C.: Association of the ABCB1 gene polymorphisms 2677GhT/A and 3435ChT with clinical outcomes of paclitaxel monotherapy in metastatic breast cancer patients. Ann. Oncol., 20: 272®277 ¤2009¥. Gonzalez, T. P., Mucenic, T., Brenol, J. C., Xavier, R. M., Schiengold, M. and Chies, J. A.: ABCB1 C1236T, G2677T/A and C3435T polymorphisms in systemic lupus erythematosus patients. Braz. J. Med. Biol. Res., 41: 769®772 ¤2008¥. Yasar, U., Babaoglu, M. O. and Bozkurt, A.: Disposition of a CYP2C9 phenotyping agent, losartan, is not influenced by the common 3435C h T variation of the drug transporter gene ABCB1 ¤MDR1¥. Basic Clin. Pharmacol. Toxicol., 103: 176®179 ¤2008¥. Xu, P., Jiang, Z. P., Zhang, B. K., Tu, J. Y. and Li, H. D.: Impact of MDR1 haplotypes derived from C1236T, G2677T/A and C3435T on the pharmacokinetics of single-dose oral digoxin in healthy Chinese volunteers. Pharmacology, 82: 221®227 ¤2008¥. Kuzman, M. R., Medved, V., Bozina, N., Hotujac, L., Sain, I. and Bilusic, H.: The influence of 5-HT¤2C¥ and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients. Psychiatry Res., 160: 308®315 ¤2008¥. Gunes, A., Spina, E., Dahl, M. L. and Scordo, M. G.: ABCB1 polymorphisms influence steady-state plasma levels of 9-hydrox-

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yrisperidone and risperidone active moiety. Ther. Drug Monit., 30: 628®633 ¤2008¥. De Iudicibus, S., Castronovo, G., Gigante, A., Stocco, G., Decorti, G., Di Lenarda, R. and Bartoli, F.: Role of MDR1 gene polymorphisms in gingival overgrowth induced by cyclosporine in transplant patients. J. Periodontal Res., 43: 665®672 ¤2008¥. Schaich, M., Kestel, L., Pfirrmann, M., Robel, K., Illmer, T., Kramer, M., Dill, C., Ehninger, G., Schackert, G. and Krex, D.: A MDR1 ¤ABCB1¥ gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients. Ann. Oncol., 20: 175®181 ¤2009¥. Sugimoto, M., Furuta, T., Shirai, N., Kodaira, C., Nishino, M., Yamade, M., Ikuma, M., Sugimura, H., Ishizaki, T. and Hishida, A.: MDR1 C3435T polymorphism has no influence on developing Helicobacter pylori infection-related gastric cancer and peptic ulcer in Japanese. Life Sci., 83: 301®304 ¤2008¥. Jamroziak, K., Balcerczak, E., Calka, K., Piaskowski, S., Urbanska-Rys, H., Salagacka, A., Mirowski, M. and Robak, T.: Polymorphisms and haplotypes in the multidrug resistance 1 gene ¤MDR1/ABCB1¥ and risk of multiple myeloma. Leuk. Res., 33: 332®335 ¤2009¥. Sissung, T. M., Baum, C. E., Deeken, J., Price, D. K., AragonChing, J., Steinberg, S. M., Dahut, W., Sparreboom, A. and Figg, W. D.: ABCB1 genetic variation influences the toxicity and clinical outcome of patients with androgen-independent prostate cancer treated with docetaxel. Clin. Cancer Res., 14: 4543®4549 ¤2008¥. Beringer, P. M., Kriengkauykiat, J., Zhang, X., Hidayat, L., Liu, S., Louie, S., Synold, T., Burckart, G. J., Rao, P. A., Shapiro, B. and Gill, M.: Lack of effect of P-glycoprotein inhibition on renal clearance of dicloxacillin in patients with cystic fibrosis. Pharmacotherapy, 28: 883®894 ¤2008¥. Mihaljevic Peles, A., Bozina, N., Sagud, M., Rojnic Kuzman, M. and Lovric, M.: MDR1 gene polymorphism: therapeutic response to paroxetine among patients with major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry, 32: 1439®1444 ¤2008¥. Dulucq, S., Bouchet, S., Turcq, B., Lippert, E., Etienne, G., Reiffers, J., Molimard, M., Krajinovic, M. and Mahon, F. X.: Multidrug resistance gene ¤MDR1¥ polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood, 112: 2024®2027 ¤2008¥. Hesselink, D. A., van Schaik, R. H., Nauta, J. and van Gelder, T.: A drug transporter for all ages? ABCB1 and the developmental pharmacogenetics of cyclosporine. Pharmacogenomics, 9: 783®789 ¤2008¥. Zhang, Y., Jiang, X. H., Hu, Y. Q., Li, Z. R., Su, L., Wang, Z. G. and Ma, G.: MDR1 genotypes do not influence the absorption of a single oral dose of 600 mg valacyclovir in healthy Chinese Han ethnic males. Br. J. Clin. Pharmacol., 66: 247®254 ¤2008¥. Ichihara, S., Yamada, Y., Kato, K., Hibino, T., Yokoi, K., Matsuo, H., Kojima, T., Watanabe, S., Metoki, N., Yoshida, H., Satoh, K., Aoyagi, Y., Yasunaga, A., Park, H., Tanaka, M. and Nozawa, Y.: Association of a polymorphism of ABCB1 with obesity in Japanese individuals. Genomics, 91: 512®516 ¤2008¥. Levran, O., OöHara, K., Peles, E., Li, D., Barral, S., Ray, B., Borg, L., Ott, J., Adelson, M. and Kreek, M. J.: ABCB1 ¤MDR1¥ genetic variants are associated with methadone doses required for effective treatment of heroin dependence. Hum. Mol. Genet., 17: 2219®2227 ¤2008¥. Maggini, V., Buda, G., Martino, A., Presciuttini, S., Galimberti, S., Orciuolo, E., Barale, R., Petrini, M. and Rossi, A. M.: MDR1 diplotypes as prognostic markers in multiple myeloma. Pharmacogenet. Genomics, 18: 383®389 ¤2008¥.

167¥ Maruyama, K., Harada, S., Yokoyama, A., Naruse, S., Hirota, M., Nishimori, I. and Otsuki, M.: Association analysis among polymorphisms of the various genes and chronic alcoholic pancreatitis. J. Gastroenterol. Hepatol., 23: S69®S72 ¤2008¥. 168¥ Lal, S., Wong, Z. W., Sandanaraj, E., Xiang, X., Ang, P. C., Lee, E. J. and Chowbay, B.: Influence of ABCB1 and ABCG2 polymorphisms on doxorubicin disposition in Asian breast cancer patients. Cancer Sci., 99: 816®823 ¤2008¥. 169¥ Pan, W., Ryu, J. Y., Shon, J. H., Song, I. S., Liu, K. H., Sunwoo, Y. E., Kang, W. and Shin, J. G.: Dietary salt does not influence the disposition of verapamil enantiomers in relation to efflux transporter ABCB1 genetic polymorphism in healthy Korean subjects. Xenobiotica, 38: 422®434 ¤2008¥. 170¥ Aarnoudse, A. J., Dieleman, J. P., Visser, L. E., Arp, P. P., van der Heiden, I. P., van Schaik, R. H., Molokhia, M., Hofman, A., Uitterlinden, A. G. and Stricker, B. H.: Common ATP-binding cassette B1 variants are associated with increased digoxin serum concentration. Pharmacogenet. Genomics, 18: 299® 305 ¤2008¥. 171¥ Basic, S., Hajnsek, S., Bozina, N., Filipcic, I., Sporis, D., Mislov, D. and Posavec, A.: The influence of C3435T polymorphism of ABCB1 gene on penetration of phenobarbital across the bloodbrain barrier in patients with generalized epilepsy. Seizure, 17: 524®530 ¤2008¥. 172¥ Ross, J. R., Riley, J., Taegetmeyer, A. B., Sato, H., Gretton, S., du Bois, R. M. and Welsh, K. I.: Genetic variation and response to morphine in cancer patients: catechol-O-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects. Cancer, 112: 1390®1403 ¤2008¥. 173¥ Yang, X. Y. and Xu, D. H.: MDR1 ¤ABCB1¥ gene polymorphisms associated with steroid-induced osteonecrosis of femoral head in systemic lupus erythematosus. Pharmazie, 62: 930®932 ¤2007¥. 174¥ Turgut, G., Kurt, E., Sengul, C., Alatas, G., Kursunluoglu, R., Oral, T., Turgut, S. and Herken, H.: Association of MDR1 C3435T polymorphism with bipolar disorder in patients treated with valproic acid. Mol. Biol. Rep., 36: 495®499 ¤2009¥. 175¥ Ozgon, G. O., Bebek, N., Gul, G. and Cine, N.: Association of MDR1 ¤C3435T¥ polymorphism and resistance to carbamazepine in epileptic patients from Turkey. Eur. Neurol., 59: 67®70 ¤2008¥. 176¥ Mihaljević-Peles, A., Bozina, N. and Sagud, M.: Pharmacogenetics in modern psychiatry. Psychiatr. Danub., 19: 231®233 ¤2007¥. 177¥ Uhr, M., Tontsch, A., Namendorf, C., Ripke, S., Lucae, S., Ising, M., Dose, T., Ebinger, M., Rosenhagen, M., Kohli, M., Kloiber, S., Salyakina, D., Bettecken, T., Specht, M., Pütz, B., Binder, E. B., Müller-Myhsok, B. and Holsboer, F.: Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron, 57: 203®209 ¤2008¥. 178¥ Kato, M., Fukuda, T., Serretti, A., Wakeno, M., Okugawa, G., Ikenaga, Y., Hosoi, Y., Takekita, Y., Mandelli, L., Azuma, J. and Kinoshita, T.: ABCB1 ¤MDR1¥ gene polymorphisms are associated with the clinical response to paroxetine in patients with major depressive disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry, 32: 398®404 ¤2008¥. 179¥ Campa, D., Gioia, A., Tomei, A., Poli, P. and Barale, R.: Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin. Pharmacol. Ther., 83: 559®566 ¤2008¥. 180¥ Turgut, G., Baştemir, M., Turgut, S., Akin, F., Kursunluoglu, R. and Kaptanoğlu, B.: P-glycoprotein polymorphism in hypo- and hyper-thyroidism patients. Mol. Biol. Rep., 35: 693®698 ¤2008¥. 181¥ Sam, S. S., Thomas, V., Sivagnanam, K., Reddy, K. S., Surianarayanan, G. and Chandrasekaran, A.: ABCB1 genetic polymorphism and risk of upper aerodigestive tract cancers among

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

Human ABCB1 and ABCG2 Gene Polymorphisms

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smokers, tobacco chewers and alcoholics in an Indian population. Pharmacogenet. Genomics, 17: 861®866 ¤2007¥. Pan, J. H., Han, J. X., Wu, J. M., Sheng, L. J., Huang, H. N. and Yu, Q. Z.: MDR1 single nucleotide polymorphisms predict response to vinorelbine-based chemotherapy in patients with nonsmall cell lung cancer. Respiration, 75: 380®385 ¤2008¥. Gréen, H., Söderkvist, P., Rosenberg, P., Horvath, G. and Peterson, C.: ABCB1 G1199A polymorphism and ovarian cancer response to paclitaxel. J. Pharm. Sci., 97: 2045®2048 ¤2008¥. Furuta, T., Sugimoto, M., Shirai, N., Matsushita, F., Nakajima, H., Kumagai, J., Senoo, K., Kodaira, C., Nishino, M., Yamade, M., Ikuma, M., Watanabe, H., Umemura, K., Ishizaki, T. and Hishida, A.: Effect of MDR1 C3435T polymorphism on cure rates of Helicobacter pylori infection by triple therapy with lansoprazole, amoxicillin and clarithromycin in relation to CYP 2C19 genotypes and 23S rRNA genotypes of H. pylori. Aliment. Pharmacol. Ther., 26: 693®703 ¤2007¥. Fiedler, T., Büning, C., Reuter, W., Pitre, G., Gentz, E., Schmidt, H. H., Büttner, J., Ockenga, J., Gerloff, T., Meisel, C., Lochs, H., Roots, I., Köpke, K. and Johne, A.: Possible role of MDR1 two-locus genotypes for young-age onset ulcerative colitis but not Crohnös disease. Eur. J. Clin. Pharmacol., 63: 917®925 ¤2007¥. Tufan, A., Babaoglu, M. O., Akdogan, A., Yasar, U., Calguneri, M., Kalyoncu, U., Karadag, O., Hayran, M., Ertenli, A. I., Bozkurt, A. and Kiraz, S.: Association of drug transporter gene ABCB1 ¤MDR1¥ 3435C to T polymorphism with colchicine response in familial Mediterranean fever. J. Rheumatol., 34: 1540® 1544 ¤2007¥. Hattori, H., Suminoe, A., Wada, M., Koga, Y., Kohno, K., Okamura, J., Hara, T. and Matsuzaki, A.: Regulatory polymorphisms of multidrug resistance 1 ¤MDR1¥ gene are associated with the development of childhood acute lymphoblastic leukemia. Leuk. Res., 31: 1633®1640 ¤2007¥. Turgut, S., Yaren, A., Kursunluoglu, R. and Turgut, G.: MDR1 C3435T polymorphism in patients with breast cancer. Arch. Med. Res., 38: 539®544 ¤2007¥. Yasui-Furukori, N., Tsuchimine, S., Saito, M., Nakagami, T., Sato, Y. and Kaneko, S.: Association between major Multidrug Resistance 1 ¤MDR1¥ gene polymorphisms and plasma concentration of prolactin during risperidone treatment in schizophrenic patients. Prog. Neuropsychopharmacol. Biol. Psychiatry, 31: 1230® 1234 ¤2007¥. Urayama, K. Y., Wiencke, J. K., Buffler, P. A., Chokkalingam, A. P., Metayer, C. and Wiemels, J. L.: MDR1 gene variants, indoor insecticide exposure, and the risk of childhood acute lymphoblastic leukemia. Cancer Epidemiol. Biomarkers Prev., 16: 1172®1177 ¤2007¥. Gurney, H., Wong, M., Balleine, R. L., Rivory, L. P., McLachlan, A. J., Hoskins, J. M., Wilcken, N., Clarke, C. L., Mann, G. J., Collins, M., Delforce, S. E., Lynch, K. and Schran, H.: Imatinib disposition and ABCB1 ¤MDR1, P-glycoprotein¥ genotype. Clin. Pharmacol. Ther., 82: 33®40 ¤2007¥. Buda, G., Maggini, V., Galimberti, S., Martino, A., Giuliani, N., Morabito, F., Genestreti, G., Iacopino, P., Rizzoli, V., Barale, R., Rossi, A. M. and Petrini, M.: MDR1 polymorphism influences the outcome of multiple myeloma patients. Br. J. Haematol., 137: 454®456 ¤2007¥. Wu, L., Xu, X., Shen, J., Xie, H., Yu, S., Liang, T., Wang, W., Shen, Y., Zhang, M. and Zheng, S.: MDR1 gene polymorphisms and risk of recurrence in patients with hepatocellular carcinoma after liver transplantation. J. Surg. Oncol., 96: 62®68 ¤2007¥. Kang, H. A., Cho, H. Y. and Lee, Y. B.: The effect of MDR1 G2677T/A polymorphism on pharmacokinetics of gabapentin in healthy Korean subjects. Arch. Pharm. Res., 30: 96®101 ¤2007¥.

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195¥ Ma, Q., Brazeau, D., Zingman, B. S., Reichman, R. C., Fischl, M. A., Gripshover, B. M., Venuto, C. S., Slish, J. C., DiFrancesco, R., Forrest, A. and Morse, G. D.: Multidrug resistance 1 polymorphisms and trough concentrations of atazanavir and lopinavir in patients with HIV. Pharmacogenomics, 8: 227®235 ¤2007¥. 196¥ Mrozikiewicz, P. M., Seremak-Mrozikiewicz, A., Semczuk, A., Landt, O., Breborowicz, G. H. and Drews, K.: The significance of C3435T point mutation of the MDR1 gene in endometrial cancer. Int. J. Gynecol. Cancer, 17: 728®731 ¤2007¥. 197¥ Mendoza, J. L., Urcelay, E., Lana, R., Martín, M. C., López, N., Guijarro, L. G., Mayol, J. A., Taxonera, C., de la Concha, E. G., Peña, A. S. and Díaz-Rubio, M.: MDR1 polymorphisms and response to azathioprine therapy in patients with Crohnös disease. Inflamm. Bowel Dis., 13: 585®590 ¤2007¥. 198¥ Ardizzone, S., Maconi, G., Bianchi, V., Russo, A., Colombo, E., Cassinotti, A., Penati, C., Tenchini, M. L. and Bianchi Porro, G.: Multidrug resistance 1 gene polymorphism and susceptibility to inflammatory bowel disease. Inflamm. Bowel Dis., 13: 516®523 ¤2007¥. 199¥ Park, H. J., Shinn, H. K., Ryu, S. H., Lee, H. S., Park, C. S. and Kang, J. H.: Genetic polymorphisms in the ABCB1 gene and the effects of fentanyl in Koreans. Clin. Pharmacol. Ther., 81: 539®546 ¤2007¥. 200¥ Miura, M., Satoh, S., Tada, H., Saito, M., Kagaya, H., Inoue, K., Sagae, Y., Kanno, S., Ishikawa, M., Habuchi, T. and Suzuki, T.: Influence of ABCB1 C3435T polymorphism on the pharmacokinetics of lansoprazole and gastroesophageal symptoms in Japanese renal transplant recipients classified as CYP2C19 extensive metabolizers and treated with tacrolimus. Int. J. Clin. Pharmacol. Ther., 44: 605®613 ¤2006¥. 201¥ Takatori, R., Takahashi, K. A., Tokunaga, D., Hojo, T., Fujioka, M., Asano, T., Hirata, T., Kawahito, Y., Satomi, Y., Nishino, H., Tanaka, T., Hirota, Y. and Kubo, T.: ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis patients. Clin. Exp. Rheumatol., 24: 546®554 ¤2006¥. 202¥ Coller, J. K., Barratt, D. T., Dahlen, K., Loennechen, M. H. and Somogyi, A. A.: ABCB1 genetic variability and methadone dosage requirements in opioid-dependent individuals. Clin. Pharmacol. Ther., 80: 682®690 ¤2006¥. 203¥ Rodríguez-Nóvoa, S., Martín-Carbonero, L., Barreiro, P., González-Pardo, G., Jiménez-Nácher, I., González-Lahoz, J. and Soriano, V.: Genetic factors influencing atazanavir plasma concentrations and the risk of severe hyperbilirubinemia. AIDS, 21: 41®46 ¤2007¥. 204¥ Gervasini, G., Carrillo, J. A., Garcia, M., San Jose, C., Cabanillas, A. and Benitez, J.: Adenosine triphosphate-binding cassette B1 ¤ABCB1¥ ¤multidrug resistance 1¥ G2677T/A gene polymorphism is associated with high risk of lung cancer. Cancer, 107: 2850®2857 ¤2006¥. 205¥ Bozina, N., Kuzman, M. R., Medved, V., Jovanovic, N., Sertic, J. and Hotujac, L.: Associations between MDR1 gene polymorphisms and schizophrenia and therapeutic response to olanzapine in female schizophrenic patients. J. Psychiatr. Res., 42: 89®97 ¤2008¥. 206¥ Taubert, D., von Beckerath, N., Grimberg, G., Lazar, A., Jung, N., Goeser, T., Kastrati, A., Schömig, A. and Schömig, E.: Impact of P-glycoprotein on clopidogrel absorption. Clin. Pharmacol. Ther., 80: 486®501 ¤2006¥. 207¥ Jamroziak, K., Balcerczak, E., Smolewski, P., Robey, R. W., Cebula, B., Panczyk, M., Kowalczyk, M., Szmigielska-Kapłon, A., Mirowski, M., Bates, S. E. and Robak, T.: MDR1 ¤ABCB1¥ gene polymorphism C3435T is associated with P-glycoprotein activity in B-cell chronic lymphocytic leukemia. Pharmacol. Rep., 58: 720®728 ¤2006¥.

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208¥ Xing, Q., Gao, R., Li, H., Feng, G., Xu, M., Duan, S., Meng, J., Zhang, A., Qin, S. and He, L.: Polymorphisms of the ABCB1 gene are associated with the therapeutic response to risperidone in Chinese schizophrenia patients. Pharmacogenomics, 7: 987®993 ¤2006¥. 209¥ Lin, Y. C., Ellingrod, V. L., Bishop, J. R. and Miller, D. D.: The relationship between P-glycoprotein ¤PGP¥ polymorphisms and response to olanzapine treatment in schizophrenia. Ther. Drug Monit., 28: 668®672 ¤2006¥. 210¥ Aarnoudse, A. L., van Schaik, R. H., Dieleman, J., Molokhia, M., van Riemsdijk, M. M., Ligthelm, R. J., Overbosch, D., van der Heiden, I. P. and Stricker, B. H.: MDR1 gene polymorphisms are associated with neuropsychiatric adverse effects of mefloquine. Clin. Pharmacol. Ther., 80: 367®374 ¤2006¥. 211¥ Sissung, T. M., Mross, K., Steinberg, S. M., Behringer, D., Figg, W. D., Sparreboom, A. and Mielke, S.: Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia. Eur. J. Cancer, 42: 2893®2896 ¤2006¥. 212¥ Drozdzik, M., Rudas, T., Pawlik, A., Kurzawski, M., Czerny, B., Gornik, W. and Herczynska, M.: The effect of 3435ChT MDR1 gene polymorphism on rheumatoid arthritis treatment with disease-modifying antirheumatic drugs. Eur. J. Clin. Pharmacol., 62: 933®937 ¤2006¥. 213¥ Haas, D. W., Bartlett, J. A., Andersen, J. W., Sanne, I., Wilkinson, G. R., Hinkle, J., Rousseau, F., Ingram, C. D., Shaw, A., Lederman, M. M. and Kim, R. B.: Adult AIDS Clinical Trials Group: Pharmacogenetics of nevirapine-associated hepatotoxicity: an Adult AIDS Clinical Trials Group collaboration. Clin. Infect. Dis., 43: 783®786 ¤2006¥. 214¥ Kim, K. A., Park, P. W. and Park, J. Y.: Effect of ABCB1 ¤MDR1¥ haplotypes derived from G2677T/C3435T on the pharmacokinetics of amlodipine in healthy subjects. Br. J. Clin. Pharmacol., 63: 53®58 ¤2007¥. 215¥ Leschziner, G., Jorgensen, A. L., Andrew, T., Pirmohamed, M., Williamson, P. R., Marson, A. G., Coffey, A. J., Middleditch, C., Rogers, J., Bentley, D. R., Chadwick, D. W., Balding, D. J. and Johnson, M. R.: Clinical factors and ABCB1 polymorphisms in prediction of antiepileptic drug response: a prospective cohort study. Lancet Neurol., 5: 668®676 ¤2006¥. 216¥ Kim, D. H., Park, J. Y., Sohn, S. K., Lee, N. Y., Suh, J. S. and Lee, K. B.: The association between multidrug resistance-1 gene polymorphisms and outcomes of allogeneic HLA-identical stem cell transplantation. Haematologica, 91: 848®851 ¤2006¥. 217¥ Dilger, K., Cascorbi, I., Grünhage, F., Hohenester, S., Sauerbruch, T. and Beuers, U.: Multidrug resistance 1 genotype and disposition of budesonide in early primary biliary cirrhosis. Liver Int., 26: 285®290 ¤2006¥. 218¥ Cho, H. Y., Park, S. A. and Lee, Y. B.: Improvement and validation of an HPLC method for examining the effects of the MDR1 gene polymorphism on sparfloxacin pharmacokinetics. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 834: 84®92 ¤2006¥. 219¥ Sohn, J. W., Lee, S. Y., Lee, S. J., Kim, E. J., Cha, S. I., Kim, C. H., Lee, J. T., Jung, T. H. and Park, J. Y.: MDR1 polymorphisms predict the response to etoposide-cisplatin combination chemotherapy in small cell lung cancer. Jpn. J. Clin. Oncol., 36: 137®141 ¤2006¥. 220¥ Gréen, H., Söderkvist, P., Rosenberg, P., Horvath, G. and Peterson, C.: mdr-1 single nucleotide polymorphisms in ovarian cancer tissue: G2677T/A correlates with response to paclitaxel chemotherapy. Clin. Cancer Res., 12: 854®859 ¤2006¥. 221¥ Meisel, P., Giebel, J., Kunert-Keil, C., Dazert, P., Kroemer, H. K. and Kocher, T.: MDR1 gene polymorphisms and risk of gingival hyperplasia induced by calcium antagonists. Clin. Pharmacol. Ther., 79: 62®71 ¤2006¥.

222¥ Rodríguez Nóvoa, S., Barreiro, P., Rendón, A., Barrios, A., Corral, A., Jiménez-Nacher, I., González-Lahoz, J. and Soriano, V.: Plasma levels of atazanavir and the risk of hyperbilirubinemia are predicted by the 3435CGT polymorphism at the multidrug resistance gene 1. Clin. Infect. Dis., 42: 291®295 ¤2006¥. 223¥ Kim, K. A., Joo, H. J. and Park, J. Y.: Effect of ABCG2 genotypes on the pharmacokinetics of A771726, an active metabolite of prodrug leflunomide, and association of A771726 exposure with serum uric acid level. Eur. J. Clin. Pharmacol., 67: 129®134 ¤2011¥. 224¥ Phipps-Green, A. J., Hollis-Moffatt, J. E., Dalbeth, N., Merriman, M. E., Topless, R., Gow, P. J., Harrison, A. A., Highton, J., Jones, P. B., Stamp, L. K. and Merriman, T. R.: A strong role for the ABCG2 gene in susceptibility to gout in New Zealand Pacific Island and Caucasian, but not Māori, case and control sample sets. Hum. Mol. Genet., 19: 4813®4819 ¤2010¥. 225¥ Takahashi, N., Miura, M., Scott, S. A., Kagaya, H., Kameoka, Y., Tagawa, H., Saitoh, H., Fujishima, N., Yoshioka, T., Hirokawa, M. and Sawada, K.: Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia. J. Hum. Genet., 55: 731®737 ¤2010¥. 226¥ Tabara, Y., Kohara, K., Kawamoto, R., Hiura, Y., Nishimura, K., Morisaki, T., Kokubo, Y., Okamura, T., Tomoike, H., Iwai, N. and Miki, T.: Association of four genetic loci with uric acid levels and reduced renal function: the J-SHIPP Suita study. Am. J. Nephrol., 32: 279®286 ¤2010¥. 227¥ Yamagishi, K., Tanigawa, T., Kitamura, A., Köttgen, A., Folsom, A. R. and Iso, H.: CIRCS Investigators: The rs2231142 variant of the ABCG2 gene is associated with uric acid levels and gout among Japanese people. Rheumatology ¤Oxford¥, 49: 1461®1465 ¤2010¥. 228¥ Stamp, L. K., Chapman, P. T., OöDonnell, J. L., Zhang, M., James, J., Frampton, C., Barclay, M. L., Kennedy, M. A. and Roberts, R. L.: Polymorphisms within the folate pathway predict folate concentrations but are not associated with disease activity in rheumatoid arthritis patients on methotrexate. Pharmacogenet. Genomics, 20: 367®376 ¤2010¥. 229¥ Bailey, K. M., Romaine, S. P., Jackson, B. M., Farrin, A. J., Efthymiou, M., Barth, J. H., Copeland, J., McCormack, T., Whitehead, A., Flather, M. D., Samani, N. J., Nixon, J., Hall, A. S. and Balmforth, A. J.: SPACE ROCKET Trial Group: Hepatic metabolism and transporter gene variants enhance response to rosuvastatin in patients with acute myocardial infarction: the GEOSTAT-1 Study. Circ. Cardiovasc. Genet., 3: 276®285 ¤2010¥. 230¥ Steeghs, N., Mathijssen, R. H., Wessels, J. A., de Graan, A. J., van der Straaten, T., Mariani, M., Laffranchi, B., Comis, S., de Jonge, M. J., Gelderblom, H. and Guchelaar, H. J.: Influence of pharmacogenetic variability on the pharmacokinetics and toxicity of the aurora kinase inhibitor danusertib. Invest. New Drugs, 29: 953®962 ¤2011¥. 231¥ Tomlinson, B., Hu, M., Lee, V. W., Lui, S. S., Chu, T. T., Poon, E. W., Ko, G. T., Baum, L., Tam, L. S. and Li, E. K.: ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin. Clin. Pharmacol. Ther., 87: 558®562 ¤2010¥. 232¥ Brandstätter, A., Lamina, C., Kiechl, S., Hunt, S. C., Coassin, S., Paulweber, B., Kramer, F., Summerer, M., Willeit, J., Kedenko, L., Adams, T. D. and Kronenberg, F.: Sex and age interaction with genetic association of atherogenic uric acid concentrations. Atherosclerosis, 210: 474®478 ¤2010¥. 233¥ Steeghs, N., Gelderblom, H., Wessels, J., Eskens, F. A., de Bont, N., Nortier, J. W. and Guchelaar, H. J.: Pharmacogenetics of telatinib, a VEGFR-2 and VEGFR-3 tyrosine kinase inhibitor,

Copyright © 2012 by the Japanese Society for the Study of Xenobiotics (JSSX)

Human ABCB1 and ABCG2 Gene Polymorphisms

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used in patients with solid tumors. Invest. New Drugs, 29: 137®143 ¤2011¥. Keskitalo, J. E., Pasanen, M. K., Neuvonen, P. J. and Niemi, M.: Different effects of the ABCG2 c.421ChA SNP on the pharmacokinetics of fluvastatin, pravastatin and simvastatin. Pharmacogenomics, 10: 1617®1624 ¤2009¥. Cha, P. C., Mushiroda, T., Zembutsu, H., Harada, H., Shinoda, N., Kawamoto, S., Shimoyama, R., Nishidate, T., Furuhata, T., Sasaki, K., Hirata, K. and Nakamura, Y.: Single nucleotide polymorphism in ABCG2 is associated with irinotecan-induced severe myelosuppression. J. Hum. Genet., 54: 572®580 ¤2009¥. Cotte, S., von Ahsen, N., Kruse, N., Huber, B., Winkelmann, A., Zettl, U. K., Starck, M., König, N., Tellez, N., Dörr, J., Paul, F., Zipp, F., Lühder, F., Koepsell, H., Pannek, H., Montalban, X., Gold, R. and Chan, A.: ABC-transporter genepolymorphisms are potential pharmacogenetic markers for mitoxantrone response in multiple sclerosis. Brain, 132: 2517® 2530 ¤2009¥. Kim, D. H., Sriharsha, L., Xu, W., Kamel-Reid, S., Liu, X., Siminovitch, K., Messner, H. A. and Lipton, J. H.: Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin. Cancer Res., 15: 4750®4758 ¤2009¥. Adkison, K. K., Vaidya, S. S., Lee, D. Y., Koo, S. H., Li, L., Mehta, A. A., Gross, A. S., Polli, J. W., Humphreys, J. E., Lou, Y. and Lee, E. J.: Oral sulfasalazine as a clinical BCRP probe substrate: pharmacokinetic effects of genetic variation ¤C421A¥ and pantoprazole coadministration. J. Pharm. Sci., 99: 1046®1062 ¤2010¥. Woodward, O. M., Köttgen, A., Coresh, J., Boerwinkle, E., Guggino, W. B. and Köttgen, M.: Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc. Natl. Acad. Sci. USA, 106: 10338®10342 ¤2009¥. Keskitalo, J. E., Zolk, O., Fromm, M. F., Kurkinen, K. J., Neuvonen, P. J. and Niemi, M.: ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin. Clin. Pharmacol. Ther., 86: 197®203 ¤2009¥. Kim, I. S., Kim, H. G., Kim, D. C., Eom, H. S., Kong, S. Y., Shin, H. J., Hwang, S. H., Lee, E. Y. and Lee, G. W.: ABCG2 Q141K polymorphism is associated with chemotherapy-induced diarrhea in patients with diffuse large B-cell lymphoma who received frontline rituximab plus cyclophosphamide/doxorubicin/ vincristine/prednisone chemotherapy. Cancer Sci., 99: 2496®2501 ¤2008¥. Luke, M. M., OöMeara, E. S., Rowland, C. M., Shiffman, D.,

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Bare, L. A., Arellano, A. R., Longstreth, W. T., Jr., Lumley, T., Rice, K., Tracy, R. P., Devlin, J. J. and Psaty, B. M.: Gene variants associated with ischemic stroke: the cardiovascular health study. Stroke, 40: 363®368 ¤2009¥. Petain, A., Kattygnarath, D., Azard, J., Chatelut, E., Delbaldo, C., Geoerger, B., Barrois, M., Séronie-Vivien, S., LeCesne, A. and Vassal, G.: Innovative Therapies with Children with Cancer European consortium: Population pharmacokinetics and pharmacogenetics of imatinib in children and adults. Clin. Cancer Res., 14: 7102®7109 ¤2008¥. Campa, D., Pardini, B., Naccarati, A., Vodickova, L., Novotny, J., Försti, A., Hemminki, K., Barale, R., Vodicka, P. and Canzian, F.: A gene-wide investigation on polymorphisms in the ABCG2/BRCP transporter and susceptibility to colorectal cancer. Mutat. Res., 645: 56®60 ¤2008¥. Adkison, K. K., Vaidya, S. S., Lee, D. Y., Koo, S. H., Li, L., Mehta, A. A., Gross, A. S., Polli, J. W., Lou, Y. and Lee, E. J.: The ABCG2 C421A polymorphism does not affect oral nitrofurantoin pharmacokinetics in healthy Chinese male subjects. Br. J. Clin. Pharmacol., 66: 233®239 ¤2008¥. Urquhart, B. L., Ware, J. A., Tirona, R. G., Ho, R. H., Leake, B. F., Schwarz, U. I., Zaher, H., Palandra, J., Gregor, J. C., Dresser, G. K. and Kim, R. B.: Breast cancer resistance protein ¤ABCG2¥ and drug disposition: intestinal expression, polymorphisms and sulfasalazine as an in vivo probe. Pharmacogenet. Genomics, 18: 439®448 ¤2008¥. Kim, H. S., Sunwoo, Y. E., Ryu, J. Y., Kang, H. J., Jung, H. E., Song, I. S., Kim, E. Y., Shim, J. C., Shon, J. H. and Shin, J. G.: The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Br. J. Clin. Pharmacol., 64: 645®654 ¤2007¥. Hu, L. L., Wang, X. X., Chen, X., Chang, J., Li, C., Zhang, Y., Yang, J., Jiang, W. and Zhuang, S. M.: BCRP gene polymorphisms are associated with susceptibility and survival of diffuse large B-cell lymphoma. Carcinogenesis, 28: 1740®1744 ¤2007¥. Hahn, N. M., Marsh, S., Fisher, W., Langdon, R., Zon, R., Browning, M., Johnson, C. S., Scott-Horton, T. J., Li, L., McLeod, H. L. and Sweeney, C. J.: Hoosier Oncology Group randomized phase II study of docetaxel, vinorelbine, and estramustine in combination in hormone-refractory prostate cancer with pharmacogenetic survival analysis. Clin. Cancer Res., 12: 6094®6099 ¤2006¥. Korenaga, Y., Naito, K., Okayama, N., Hirata, H., Suehiro, Y., Hamanaka, Y., Matsuyama, H. and Hinoda, Y.: Association of the BCRP C421A polymorphism with nonpapillary renal cell carcinoma. Int. J. Cancer, 117: 431®434 ¤2005¥.

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