Genetic Polymorphism of Human Cytochrome P450 Involved in Drug Metabolism

Drug Metabol. Pharmacokin. 17 (3): 167–189 (2002).

Review Genetic Polymorphism of Human Cytochrome P450 Involved in Drug Metabolism Kiyoshi NAGATA and Yasushi YAMAZOE Department of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan Summary: Recent advances in human gene analysis promoted by the human genome project have brought us a massive amount of information. These data can be seen and analyzed by personal computer through individual Web sites. As a result, the best use of bioinformatic is essential for recent molecular biology research. Genetic polymorphism of drug­metabolizing enzymes in‰uences individual drug e‹ca­ cy and safety through the alteration of pharmacokinetics and disposition of drugs. Considerable amounts of data have now accumulated as allelic diŠerences of various drug metabolizing enzymes. Current un­ derstanding of genotype information on cytochrome P450 is hereby summarized, based on the Web site for their use in individual optimization of drug therapy. Key words: cytochrome P450; drug metabolizing enzymes; polymorphism; genotype; individual diŠerence and without ambiguity, but it can be troublesome, be­ cause it is di‹cult to distinguish whether the gene is der­ ived from humans or experimental animals. With this system, italics are used to show a gene. The positions of the genes on human chromosome have been identiˆed from recent gene studies. Several Web sites for the P450 nomenclature and their polymorphisms are available and updated frequently. Setting the standard nomencla­ ture for drug­metabolizing enzymes other than P450 is also under way.8–10) Web site address for a typical en­ zyme group and its nomenclature and are shown in Table 1. Polymorphism of human drug metabolism is distin­ guished by phenotype and genotype. The phenotype (expressed type) is distinguished by activity or content of an enzyme. Individuals having normal metabolic ac­ tivity are called EM (extensive metabolizer) and defec­ tive individuals are called PM (poor metabolizer).11) On the other hand, genotype is distinguished from mutation detected by the DNA analysis of biological materials such as blood or hair root. Thus, PM W EM phenotyping may be subdivided into several distinct gene types. Moreover, the genotyping is capable of analyzing many diŠerent genes by using the same sample. When diagno­ sis is done with only speciˆc domains, misidentiˆcation may be caused by judging as a normal for a defect and unknown allele.

Introduction Enzymatic oxidation reaction is often rate­limited for the fate of a drug in the body. Cytochrome P450 (P450) is mostly responsible for that reaction. Therefore, it is expected that a dysfunction of P450 may lead to unex­ pected drug eŠects and toxicity.1,2) P450 is one of the heme proteins distributed over the life kingdom from bacteria to humans and consists of a supergene family.3) Among the supergene families, P450s, including family 1 to 4 (CYP1­4), are involved in metabolisms of foreign chemicals and drugs.1) P450s catalyzing biotransforma­ tion of steroids, such as CYP7, CYP11, and CYP21, are also expressed in humans. The gene mutation of these enzymes causes congenital disorders of steroid metabo­ lism,4–6) although those enzymes are rarely involved in the metabolism of foreign compounds. Most of the drug­metabolizing enzymes have had their names changed.3) This originated in the gene der­ ived from the conventional activity or characteristic of the protein. For example, P450 is now called CYP, which is derived from an underlined part of cytochrome P450.7) After several revisions, CYP nomenclature now consists of a family (Arabic ˆgures), subfamily (al­ phabet) and individual number based on the similarity of the amino acid sequence.7) Arabic ˆgures are given in order of discovery. This nomenclature system is simple

Received; June 5, 2002, Accepted; July 3, 2002 To whom correspondence should be addressed: Kiyoshi NAGATA, Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki­Aoba, Aoba­ku, Sendai 980­8578, Japan. Tel. +81­22­217­6828, Fax. +81­22­217­6826, E­mail: nagataki—mail.cc.tohoku.ac.jp. Footnote: Color version (pdf format) of ˆgures shown in this text can be obtained from following Web site address. (http: W xenobio.kopas. W co.jp W ) 167

Kiyoshi NAGATA and Yasushi YAMAZOE

168 Table 1. ADH ALDH CES COMT CYP FMO GST mEH NAT NQO SULT TPMT UGT

Typical drug­metabolizing enzymes and, their gene symbols and typical homepage addresses

Alcohol Dehydrogenase Aldehyde Dehydrogenase Carboxylesterase Catechol O­Methyltransferase CytochromeP450 Flavin Monooxygenase Glutathione S­Transferase Microsomal Epoxide Hydrolase Acetyltransferase Qinone Oxidoreductase Sulfotransferase Thiopurine S­Methyltransferase UDP Glucuronosyltransferase

http: W www.uchsc.edu W sp W sp W alcdbase W alcdbase.html W http: W www.uchsc.edu W sp W sp W alcdbase W alcdbase.html W ¿ http: W www3.icgeb.trieste.it W sbasesrv W cgi­bin W grsearchA.pl?151 W http: W www.chem.qmul.ac.uk W iubmb W enzyme W EC2 W 1W 1W 6.html W http: W drnelson.utmem.edu W matrix.html W ¿ http: W www3.icgeb.trieste.it W sbasesrv W cgi­bin W grsearchA.pl?771 W http: W www.cdc.gov W genetics W hugenet W reviews W glutathione.htm”Tables W http: W meropslinks.iapc.bbsrc.ac.uk W MeropsLinks W pepcards W S33p971.htm W http: W www.louisville.edu W medschool W pharmacology W NAT.html W http:W www.fccc.edu W research W labs W raftogianis W sult W index.html W http:W www.chem.qmul.ac.uk W iubmb W enzyme W EC2 W 1W 1W 67.html W http:W www.unisa.edu.au W pharmämedsci W Glucätrans W W

About Figures Figures shown in this paper represent the gene loca­ tion, nucleotide substitution and amino acid change which have been found in P450 genes involved in drug metabolism, and are drawn from data based on the Web sites of the Human Cytochrome P450 (CYP ) Allele Nomenclature Committee (http: WW www.imm.ki.se W CYPalleles W ), GeneCards (http: WW nciarray.nci.nih.gov W cards W ), Homo sapiens Map View and BLAST the Hu­ man genome (http: WW www.ncbi.nlm.nih.gov W genome W seq W HsBlast.html). ``Gene location'' indicates chromo­ some locating of individual P450 genes and the maps identiˆed previously. The parentheses represent the position of the P450 gene in the chromosome indicated with the nucleotide base. Contig No, for example, NTä010374.5 in Fig. 1A for the CYP1A1 gene represents the number which has been assembled at the National Center for Biotechnology Information (NCBI) using ˆnished and draft­throughput genomic sequence data. The parentheses indicate the length of the gene spread on the chromosome. Arrow shown at the right side of the chromosome picture indicates a map position of the P450 gene derived from Homo sapiens Map View. A number, for example, NMä000499 in Fig. 1B, represents an accession number of the CYP1A1 cDNA as the unigene representative sequence described in GeneCards. The parentheses indicate the nucleotide length of the cDNA. Exon numbers for constructing the gene and, the ˆrst and last nucleotide numbers of in­ dividual exons for unigene cDNA are also indicated in the box. The mutation positions are shown by nucleo­ tide numbers which start at the initiation codon (``A'' is given a number with 1) in the gene or cDNA. Bold letter represents an allele encoding a normal active enzyme. Letter withE represents an allele encod­ ing a low active enzyme. Bold letter underlined represents an allele expressing inactive protein. Letter withD represents an allele which increases the catalytic activity. Letter underlined represents an allele which

does not express the protein. Letter without modiˆca­ tion represents an allele in which the enzyme activity is unclear. Letter in box shown in Fig. 9A1, A2 and B expresses nucleotide mutations found in more than 4 al­ leles, which are shown in Table 2. The numbers at upper left, ``1'', and right of cDNA represent the start and end sites for translation of protein, respectively. The num­ bers of the lower site represent the ˆrst and last nucleo­ tide numbers of translation in the cDNA registered as the unigene. The parentheses represent the amino acid numbers encoded. CYP1 Family P450 called P­448 in the past is included in this group.12) The CYP1 family is composed of CYP1A and CYP1B subfamilies, including CYP1A1 and CYP1A2, and CYP1B1, respectively.3,7) Since these genes are well conserved among mammals, the same names, CYP1A1, CYP1A2 and CYP1B1, for their genes are commonly used throughout experimental animals and in humans. The substrate speciˆcity is, however, diŠerent among animal species. Thus, the human form is also called hu­ man CYP1A1 or hCYP1A1. The amino acid sequences of CYP1A1 and CYP1A2 are very similar to each other. However, clear diŠerences are found in the substrate speciˆcity and organ distribution.13) CYP1A1 and CYP1A2 have high activities for the formation of ben­ zo[a]pyrene diol epoxide and arylamine N­oxidization, respectively.2,13) Moreover, CYP1B1 is strongly involved in metabolic activation of dimethyl benzo[a]pyrene (DMBA).2,13) Although detection of CYP1A1 is di‹cult in normal organs, CYP1A1 is detected by exposure to inducers such as PCB and dioxin in tissues or cells of the whole body. Therefore, it is believed that CYP1A1 is important for oxidation of drugs in extrahepatic tissues other than liver. On the other hand, expression of CYP1A2 is mostly conˆned in the liver.2) CYP1A2 is detected constitutively. About 40­time individual varia­ tion is observed in the CYP1A2 content of livers, even if there is no evident exposure to inducers.13) CYP1B1 is

Genetic Polymorphism of Human P450

Fig. 1.

detected in cells with comparatively high proliferation, and is involved in estrogen metabolism.2,13) Therefore, CYP1B1 as well as CYP1A1 are considered to be en­ zymes functioning mostly in extrahepatic tissues.13) 1.

CYP1A1 A number of human CYP1A1 gene alleles have been identiˆed.14–20) Ten alleles, CYP1A1*1A (wild type), CYP1A1*1B, CYP1A1*1C, CYP1A1*2A, CYP1A1*2B, CYP1A1*2C, CYP1A1*3, CYP1A1*4, CYP1A1*5, and CYP1A1*6, are reported as shown in Fig. 1. Alleles from CYP1A1*2B to CYP1A1*6 (except for CYP1A1*3 ) are accompanied by amino acid changes. The relationship between these alleles and risks for carcinogenesis has been investigated. Some reports suggest the relationship between lung cancer risk and a speciˆc allele, but other studies do not support this.

169

CYP1A1.

Therefore, diagnosis using these genotypes does not yield a clear conclusion at the present time. 2.

CYP1A2 Human CYP1A2 gene alleles are also analyzed.21–28) As described above, a remarkable diŠerence is observed in the expressed level of CYP1A2 in individual human livers. At present, 13 alleles are reported as shown in Fig. 2. Alleles from CYP1A2*1B to CYP1A2*1H have nucleotide substitutions in the non­translating region of the CYP1A2 gene. On the other hand, alleles from CYP1A2*2 to CYP1A2*6 have nucleotide substitutions in the translation region causing amino acid changes. For CYP1A2*1C, in which G is replaced by A at 3858 base upstream from the translation start site (ATG), this one base substitution is suggested to reduce the transcriptional rate as a result from gel shift analysis by

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Kiyoshi NAGATA and Yasushi YAMAZOE

Fig. 2.

use of human liver nuclear extract.24) Moreover, CYP1A2*1F, with the substitution at „164CÀA near a translation start site, is suggested to in‰uence inducibili­ ty in a smoker.26) The variant type (A) shows a higher inducibility of CYP1A2 than the wild type (C), although further investigation is necessary to obtain a ˆrm con­ clusion via an increased number of individuals. CYP1A2*2 causes one base substitution from C to G in exon 2; as a result, amino acid (Phe) at the 21st was changed to Leu, since it was ˆrst found in a Chinese population.28) The allele frequency is about 0.3–0.6z. Based on the caŠeine test, the frequency of individuals with a low activity of CYP1A2 (PM) is not greatly diŠerent (about 5–15z) among a population. The gene polymorphism, which can explain the low activity in a caŠeine test, has not yet been found. Therefore, the in­ dividual diŠerences of human CYP1A2 activity might be in‰uenced environmental factors rather than gene polymorphism.29) 3.

CYP1B1 Polymorphism of the human CYP1B1 gene has been reported recently. Some alleles are found as genes

CYP1A2.

relevant to hereditary glaucoma. These data are based on the results from a study of an Arabian population in­ vestigated by Stiolov et al.30) Until now, 22 alleles have been found as shown in Fig. 3.30–33) Frame shifts causing no protein expression are observed in the CYP1B1*13, CYP1B1*15, CYP1B1*17, CYP1B1*22, CYP1B1*24 and CYP1B1*25 alleles. Splicing error due to gene dele­ tion is found in the CYP1B1*16 allele.32) Other alleles cause amino acid change, which is unclear for these functional properties. 4.

Induction and inhibition of human CYP1 forms P450s including the CYP1 family are induced or inhibited by drugs and environmental pollutants. CYP1A1, CYP1A2 and CYP1B1 are induced by tran­ scriptional activation through XRE (xenobiotic respon­ sive element) of the 5?­upstream region of each gene through the binding of a nuclear receptor, AhR (dioxin receptor).34) Therefore, charred material taken in with meals and smoking is considered to induce these P450 forms by way of activation of the AhR pathway. Poly­ morphism of the human AhR gene has been studied. Several nucleotide substitutions are found in the 5?­

Genetic Polymorphism of Human P450

Fig. 3.

upstream region and the translation domain.15,35–39) Among these alleles, AhR with amino acid changes, Val570Ile and Arg554Lys, are shown to have dimini­

171

CYP1B1.

shed the ability to induce CYP1A1, even if TCDD is added in cells overly expressing AhR.35) This type of allele is rarely found in an African population. Recent­

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Kiyoshi NAGATA and Yasushi YAMAZOE

Fig. 4.

ly, AhR repressor, which inhibits AhR function by com­ peting with AhR has been found40) and the gene poly­ morphism was also reported.41) Signiˆcant correlation is not observed between the CYP1A1 induction and the gene activation mediated by AhR among human populations. Moreover, CYP1A1 is increased after intake of omeprazole, a proton pump in­ hibitor. The molecular mechanism of the induction, however, diŠers from that of AhR. For individuals showing low CYP1A2 activity, it is di‹cult to distin­ guish whether the dysfunction is caused by gene poly­ morphism or inhibition of CYP1A2 activity by drug treatment. CYP2 Family Many P450s included in the CYP2 family have been shown to compose a number of subfamilies. At the present time, subfamilies from CYP2A to CYP2W and CYP2AA are registered in the cytochrome drnelson.utmem.edu W P450 Homepage (http: W W CytochromeP450.html). The pseudogene, which has

CYP2A6.

lost its function due to nucleotide mutation, is expected to be contained, and thus a number of P450 with a func­ tion has not been estimated exactly. Among these sub­ families, however, CYP2A (2A6, 2A7 and 2A13), CYP2B (2B6), CYP2C (2C8, 2C9, 2C18 and 2C19), CYP2D (2D6). CYP2E (2E1), CYP2F (2F1), CYP2J (2J2), CYP2R (2R1), CYP2S (2S1) and CYP2W (2W1) have been identiˆed as the gene encoding the protein in humans. Their roles in drug metabolism and gene polymorphism are not known in detail for CYP2F1, CYP2J2, CYP2R1, CYP2S1 and CYP2W1 at the present time. 1.

CYP2A6 Human P450s included in the CYP2A subfamily are CYP2A6, CYP2A7 and CYP2A13. These genes show high extents of similarity to each other and are mapped on chromosome 19 in tandem.42) CYP2A7 is the pseu­ dogene and has no function. This pseudogene causes the generation of a hybrid gene with the CYP2A6 gene. CYP2A6 is known as an enzyme catalyzing coumarin 7­

Genetic Polymorphism of Human P450

Fig. 5.

hydroxylation. Due to a large individual diŠerence of coumarin 7­hydroxylase activity, gene polymorphism has been suggested for many years.43) The gene structure was clariˆed in 1990 and 16 alleles were found as shown in Fig. 4.44–53) With alleles from CYP2A6*2 to CYP2A6*11, except for CYP2A6*3, CYP2A6*4 and CYP2A6*9, nucleotide substitutions are found in the translational domain of the CYP2A6 gene which causes amino acid changes. CYP2A6*6, CYP2A6*7, CYP2A6*8, CYP2A6*10, and CYP2A6*11 encode an enzyme in which activities are lower than the wild type. CYP2A6*2 has been known as inactive for many years due to mutation of the transla­ tional domain (Leu160His), which is suggested to yield an apoprotein without heme.45,54) CYP2A6*5 is an allele in which the amino acid at 479th is changed to Val from Gly.48) This recombinant form does not show coumarin 7­hydroxtylase activity in expressed cells. CYP2A6*9 has a mutation in TATA box (148TÀG), which results in decrease of coumarin 7­hydroxylase activity due to the low expression level of the protein.51) Interestingly,

173

CYP2B6.

gene duplication is found in the CYP2A6*1X2 allele by conversion of the CYP2A7 gene.49) CYP2A6*3 is consi­ dered to be an allele which contains some parts of the CYP2A7 gene after gene conversion.42) CYP2A6*4s are alleles of the gene defect and lack function.47,48) Racial diŠerences are observed in the frequency of these alleles. For example, CYP2A6*2 (a few z) and CYP2A6*3 (0.7z) are found in the European population, but the allele is not detected among Asian populations, includ­ ing Japanese.46) On the contrary, CYP2A6*4 is detecta­ ble as high as 10–20z in Asian populations, but is low (about 1z) in the European population.46) At present, CYP2A6*1X2 is also reported in the European population.49) CYP2A6*7 is observed at a high frequen­ cy (15.7z) in the Japanese population.55) Furthermore, CYP2A6*9 is detected at 5–7z and 15z of frequency in European and Chinese populations, respectively.51) Thus, an individual with mutated alleles of the CYP2A6 gene except for CYP2A6*8, is considered to exist at a high frequency all over the world. Since the metabolism, which converts nicotine to cotinine, depends on

174

Kiyoshi NAGATA and Yasushi YAMAZOE

Fig. 6.

CYP2A6, a correlation between smoking and the CYP2A6 genotype in lung cancer is suggested.56) Although drugs currently used are rarely metabolized by CYP2A6, fadolorol (breast cancer drug), halothane (anesthetic drug) and tegaful (anti­cancer drug) are the substrates.13) 2.

CYP2B6 CYP2B6 is known as an enzyme involved in the metabolism of iso‰urane, 3­methyl­4­aminobenzene and S­mephenytoin (N­demethylation).13,57) The ex­ pressed level of CYP2B6 in human livers is about 0.1 to 1z of total P450 content, but varies largely among in­ dividuals.13) In addition to the liver, CYP2B6 is detected in the brain, small intestine, kidney, and lung. CYP2B6 catalyzes testosterone 16a­hydroxylation, which is also catalyzed by counterparts of CYP2B in experimental animals. The induction proˆle of CYP2B6 is, however, not the same as that of experimental animals. CYP2B form is strongly induced by treatment of experimental animals with phenobarbital; particularly in rats, the

CYP2C8.

level is more than half of total P450 content. CYP2B6 is not so much elevated in human livers. The CYP2B6 gene is located on chromosome 19 with CYP2B7 (pseudogene). As mentioned previously, the CYP2A6 gene is also located on the nearby region.58) The gene polymorphism of CYP2B6 has been analyzed in 35 Eu­ ropeans, and nine point mutations were found so far.59) As shown in Fig. 5, six alleles have a nucleotide substitu­ tion with amino acid change occurring in exons 1, 4, and 5 or 9, and are termed CYP2B6*2, CYP2B6*3, CYP2B6*4, CYP2B6*5, CYP2B6*6, and CYP2B6*7.59,60) Among these alleles, individuals who have CYP2B6*6 or CYP2B6*7 are suggested to show decreased activity of S­mephenytoin demethylase.59) 3.

CYP2C8 and CYP2C9 CYP2C8 is involved in metabolism of paclitaxel (anti­ cancer drug) and ‰uvastatin (HMG CoA reductase inhibitor), and diclofenac 5­hydroxylation (anti­in‰am­ matory drug).61–63) The level of CYP2C8 in human livers is less than 1z of total P450 content. The individual

Genetic Polymorphism of Human P450

Fig. 7.

diŠerence of the CYP2C8 level has been detected by use of the anti­CYP2 antibody, and is suggested as the gene polymorphism. Recently, several alleles (CYP2C8*2, CYP2C8*3, CYP2C8*4 ) have been found (Fig. 8).64,65) CYP2C8*3 is an allele encoding a low active enzyme.65) CYP2C9 is one of the major P450s found in human livers.2,66) The level in human liver is equivalent or second only to that of CYP3A4.13) CYP2C9 is often in­ volved in metabolism of a drug containing acidic residue in its molecule. In most cases, phenytoin (anti­epilepsy drug), tolubutamide (hypoglycemia drug), warfarin (coagulant drug) and nonsteroidal anti­in‰ammatory drugs are used for the diagnostic purpose.13) Twelve alleles have been listed on the Web site. As shown in Fig. 7, ˆve alleles have been reported so far.67–72) Alleles from CYP2C9*2 to CYP2C9*5 have a single base substitution in exons and are related to decreases in enzyme activity except for CYP2C9*4 of which the enzyme activity is unclear. CYP2C9*6 causes a frame shift by one base deletion in exon 4.72) In the Japanese population, the CYP2C9*2 allele is not found. The frequency of CYP2C9*3 is a few percentage.73) The

175

CYP2C9.

frequencies of CYP2C9*2 and CYP2C9*3 are 1 and 5z in an African population, and 8 and 6z in a European population, respectively.69,74) Other gene polymorphisms of CYP2C9 in the 5?­‰anking region, which has not been registered in the Web sites of the Human CYP Allele Nomenclature Committee was also reported.75) These mutations are suspected to reduce drug­ metabolizing activity. CYP2C9 is also involved in the metabolism of many drugs, such as losartan (Angioten­ sin II receptor antagonist),76) besides the drugs men­ tioned above. However, individual diŠerences observed in these drug metabolisms cannot be explained only by these alleles. Gene analysis of the 5?­upstream region must be done to understand the diŠerence. 4.

CYP2C18 and CYP2C19 CYP2C19 was ˆrst found as an enzyme causing a deˆciency of S­mephenytoin 4?­hydroxylation.77) Dia­ zepam, omeprazole, imipramine and propranolol are also metabolized by this enzyme. CYP2C19 is mainly expressed in the liver at a few percent of the total P450 content, which is ten times lower than that of CYP2C9.

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Kiyoshi NAGATA and Yasushi YAMAZOE

Fig. 8.

Alleles shown in Fig. 8 have been found.78–81) CYP2C19 is the largest gene among human P450s involved in drug metabolism, and the whole gene has not been identiˆed. There is a 50k base gap to be identiˆed. All alleles found previously except for CYP2C19*1B (wild type), show no enzyme activity. Among these alleles, CYP2C19*2, CYP2C19*3 and CYP2C19*7 have a nucleotide muta­ tion which causes a splicing error and generation of a termination codon, respectively.77,78,82) CYP2C19*4 has a single base substitution at the translation start site (ATG).81) CYP2C19*5, CYP2C19*6 and CYP2C19*8 alleles encode inactive proteins via their amino acid changes.82,83) The high frequency of PM involved in CYP2C19 is found at 12–23z in Southeast Asian popu­ lations, including Japanese.84) As the result of previous genotyping, 70z of Japanese PM have the CYP2C19*2 allele, and the rest of most PM have the CYP2C19*3 allele.78) CYP 2C19*3 is an inherent allele type in an Asian population. Moreover, it also shows clearly the diŠerence in the eŠect of omeprazole (proton pump in­ hibitor) on disinfection of H. pylori in the stomach between genotypes.85)

CYP2C19.

Although CYP2C18 is detected in only a low amount in human livers, this P450 is also found in the gonad glands.86) Three alleles, CYP2C18*1, CYP2C18*2 (Tyr68termination codon in exon 2), and CYP2C18*3 (deˆcient of the 5?­upstream region), have been report­ ed so far (data not shown).87,88) In the Japanese popula­ tion, CYP2C19*2 and CYP2C18*3 have been detected almost at the same frequency, and it is presumed that individuals having the CYP2C19*2 allele also have the CYP2C18*3 allele.89) 5.

CYP2D6 In the late 70's, involvement of a hereditary factor on debrisoque and sparteine metabolisms were found by Smith (England) and Eichelbaum (Switzerland), respec­ tively.90,91) Now these phenomena are well known to be related to CYP2D6. This P450 is found to be a few per­ cent of the total P450 content in livers.13) A number of drugs that act on the central and W or circulatory systems are oxidized by CYP2D6.2,13) Therefore, this form has attracted the attention of many researchers. After the cloning of the CYP2D6 gene by Kimura et al. in NIH,

Genetic Polymorphism of Human P450

Fig. 9–1.

CYP2D6.

177

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Kiyoshi NAGATA and Yasushi YAMAZOE

Fig. 9–2.

large numbers of the allele have been found so far.92) This gene is located in chromosome 22 together with the pseudogenes CYP2D7 and CYP2D8 in tandem.92) However, the CYP2D6 gene was not found in the work­ ing draft sequence of the human gene in the public data­ base, which was analyzed by the recent genome project. The reason is unclear, but it is expected that the human genome DNA sample used in the project might have been isolated from an individual who has a CYP2D6 gene deletion such as the CYP2D6*5 allele. Therefore, as shown in Fig. 9, the gene location can't be estimated exactly in chromosome 22. After several revisions of its name, the genotype is now divided into 75 alleles as shown in Fig. 9 A1), A2) and B) and Table 2.92–121) Among 75 alleles, 26 alleles express protein, but CYP2D6*7, CYP2D6*12, CYP2D6*14, CYP2D6*18 and CYP2D6*40 encode inactive proteins100,108,112,118) and CYP2D6*9. CYP2D6*10, CYP2D6*17, CYP2D6*36 and CYP2D6*41 encode enzymes that decrease activi­ ty.95,97,101,122) The nucleotide mutation occurs on all nine exons rather than any speciˆc part of the CYP2D6 gene. Table 2 shows positions of the nucleotide mutation found in more than 4 alleles. Mutations at 4180 bases (GÀC) and 2850 bases (CÀT) accompanying amino

CYP2D6.

acid changes (S486T and R296C, respectively) are found in 42 and 26 alleles, respectively. It is reported that these amino acid changes do not alter the enzyme activity. These data strongly suggest that some CYP2D6 alleles have been regenerated by recombination of the CYP2D6 gene between diŠerent alleles during exchange of individuals. The frequency of PM (the phenotype) investigated with debrisoque or metoprolol is 1z or less in the Japanese population and is 5–8z in the European population.123,124) Ninety­ˆve percent of PM in the European population is explained by CYP2D6*3A, CYP2D6*3B, CYP2D6*4A–L and CYP2D6*5 alleles, and the frequency of CYP2D6*4 is the highest among these alleles.124) The frequency of CYP2D6*10, which was called CYP2D6J previously, is very high (0.4) next to the wild type in the Japanese population.125) The individual who has this allele as homo or hetero with CYP2D6*5 (about 6z in the Japanese population) is EM, but the metabolic capacity is low. These individ­ uals may be distinguished as IM (intermediate metabolizer).126) An individual with CYP2D6*2 is sug­ gested to have a normal activity.98) This allele is found at about 0.35 frequency in the European population,98) and is found at about 0.09 frequency in the Japanese population.125) Several gene duplications are found in

Genetic Polymorphism of Human P450

Table 2. Alelle

Protein

CYP2D6*40 CYP2D6*11 CYP2D6*12 CYP2D6*28 CYP2D6*29 CYP2D6*2A CYP2D6*2B CYP2D6*2E CYP2D6*35 CYP2D6*35X2D CYP2D6*41E CYP2D6*19 CYP2D6*20 CYP2D6*2C CYP2D6*2F CYP2D6*2G CYP2D6*2H CYP2D6*2J CYP2D6*2K CYP2D6*30 CYP2D6*31 CYP2D6*32 CYP2D6*8 CYP2D6*4K CYP2D6*4C CYP2D6*4E CYP2D6*10AE CYP2D6*10BE CYP2D6*36E CYP2D6*37 CYP2D6*4D CYP2D6*4A CYP2D6*4F CYP2D6*4G CYP2D6*4H CYP2D6*4L CYP2D6*39 CYP2D6*14 CYP2D6*17E CYP2D6*2D CYP2D6*4B CYP2D6*6C CYP2D6*4J CYP2D6*6A CYP2D6*6B CYP2D6*6D

CYP2D6.40 . CYP2D6.12 CYP2D6.28 CYP2D6.29 CYP2D6.2 CYP2D6.2 CYP2D6.2 CYP2D6.35 CYP2D6.35D CYP2D6.2E . . CYP2D6.2 CYP2D6.2 CYP2D6.2 CYP2D6.2 CYP2D6.2 CYP2D6.2 CYP2D6.30 CYP2D6.31 CYP2D6.32 . . . . CYP2D6.10E CYP2D6.10E CYP2D6.36E CYP2D6.37 . . . . . . CYP2D6.39 CYP2D6.14 CYP2D6.17E CYP2D6.2 . . . . . .

179

Position of nucleotide substitution found in more than 4 alleles of the CYP2D6 gene Nucleotide changes

997CÀG

1846GÀA 1846GÀA 1846GÀA 1039CÀT 1039CÀT 1039CÀT 1039CÀT 974CÀA 974CÀA 974CÀA 974CÀA

984AÀG 984AÀG 984AÀG 984AÀG

997CÀG 997CÀG 997CÀG 997CÀG 997CÀG

1846GÀA 1846GÀA 1846GÀA 1846GÀA 1846GÀA 1846GÀA

2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 2850CÀT 100CÀT 2850CÀT 100CÀT 100CÀT 100CÀT 100CÀT 100CÀT 100CÀT 100CÀT 100CÀT 100CÀT 100CÀT 100CÀT 100CÀT

1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC 1661GÀC

100CÀT 2850CÀT 2850CÀT 2850CÀT 974CÀA 984AÀG 997CÀG 1846GÀA 100CÀT 1707TÀdel 974CÀA 984AÀG 997CÀG 1846GÀA 100CÀT

4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC 4180GÀC

1661GÀC

1707TÀdel 1707TÀdel 1707TÀdel

this gene. Individuals with two or more genes of CYP2D6*2 allele (2XN) have elevated drug­metaboliz­ ing activity, and are therefore called UM (ultra­rapid metabolizer). Individuals with the 13 genes at maximum are also found.127) These variant are considered to have been generated as a result of exchange between Arabi­ ans and Europeans. The frequency of individuals with CYP2D6*17, which causes dysfunction, is higher in African populations.110,124)

6.

CYP2E1 CYP2E1 is known as an enzyme which metabolizes compounds with relatively small molecule size, such as halothane (anesthetic drug), haloalkane (organic sol­ vent), and short chain nitrosoamine.13,128) This gene is highly conserved among mammals within the CYP2 family, and is called by the same name, CYP2E1. CYP2E1 is induced by drinking alcohol.3) As the result, its content in the liver increases. Alleles reported are shown in Fig. 10.129–135) CYP2E1*1C, and CYP2E1*1D have insertion of a repeated nucleotide sequence in the

180

Kiyoshi NAGATA and Yasushi YAMAZOE

Fig. 10.

5?­upstream region.135) It is supposed that an individual with CYP2E1*1D has a remarkable increase in CYP2E1 activity after drinking. CYP2E1*2, CYP2E1*3 and CYP2E1*4 which occur in nucleotide substitution in a translation domain, are suggested to have decreased activity.133,134) CYP2E1 is an important enzyme for metabolism of an organic solvent, and is being investi­ gated as an environmental risk factor together with glutathione transferase. CYP3A Subfamily CYP3A is well known as a P450 which metabolizes drugs with large molecule sizes, and also an enzyme in­ duced by treatment with drugs such as rifampicin and dexamethasone.13) Several CYP3A forms mediating drug­metabolizing activities are found in human livers and small intestines.13,136) The expression level in human livers is about 30z of the total P450 content, but varies by 20 times among individuals.13) The mean relative content of CYP3A is supposed to be 60–70z or more of total P450 in a small intestine.13) For this reason, the CYP3A form plays very important roles for drug

CYP2E1.

metabolism at the ˆrst passage of drugs administered orally. Four CYP3A genes, CYP3A4, CYP3A5, CYP3A7, and CYP3A43, have been identiˆed in hu­ mans at present and shown to be located on chromo­ some 7 within about 200k bases.137) CYP3A43 exists as a reverse direction against another three genes. Expressed level of CYP3A4 is the highest among CYP3A forms, and 1 in 4 of individuals in the European population also express CYP3A5 in the liver.138) Moreover, CYP3A7, which is a dominant CYP3A form in em­ bryonic liver, is also detected in a low percentage of adult livers.139,140) Although CYP3A43 protein is not yet identiˆed, the mRNA is detected from gonad glands.137,141) Alleles for CYP3A4 are shown in Fig. 11; CYP3A4* 1A–1F, CYP3A4*2–14,CYP3A4*15A–B,andCYP3A4* 16–19 are known.142–149) CYP3A4*18 is reported as an allele encoding a higher active form compared to the wild type.146) To the contrary, CYP3A4*4, CYP3A4*5, CYP3A4*6 and CYP3A4*17 are reported as alleles encoding lower activity than that of the wild­type.145,146) For the CYP3A5 gene, eleven alleles are also reported

Genetic Polymorphism of Human P450

Fig. 11.

as shown in Fig. 12.150–153) Several pseudogenes (frag­ ments) are observed around these genes. In particular, CYP3AP2–1 shows the same nucleotide sequence with exon1 of the CYP3A5 gene. Moreover, an individual who has CYP3A5*1 and CYP3AP2–1*1 expresses a high level of CYP3A5.138) Alleles of CYP3A7 occurring in nucleotide mutation of the 5?­upstream region have been found and called CYP3A7*1B–E as shown in Fig. 13.138) There is about a 30­time individual diŠerence in the content of the CYP3A forms. However, alleles which can explain the

181

CYP3A4.

individual phenotype diŠerence observed in livers are not yet found. In addition, no signiˆcant correlation is observed between content in the liver and small intes­ tine. CYP3A forms are induced by a mechanism mediated by a nuclear transfactor, the pregnane X receptor (PXR).154) Steroids or bile acid as well as a number of drugs work as endogenous and exogenous inducers, respectively. The gene polymorphism of PXR is also reported.155,156) However, the mutation involved in the large individual diŠerence of the CYP3A activity was

182

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Fig. 12.

CYP3A5.

Fig. 13.

CYP3A7.

Genetic Polymorphism of Human P450

not found so far. Progress on research for analysis of the intrinsic inducer and PXR polymorphism is awaited. References Gonzalez, F. J.: The molecular biology of cytochrome P450s. Pharmacol. Rev., 40: 243–288 (1989). 2) Guengerich, F. P.: Human Cytochrome P450 enzymes: Cytochrome P450: Structure, Mechanism, and Bioche­ mistry (Second Edition), (P. R. Ortiz de Montellano ed.) Plenum press, New York, 1995, pp. 473–535. 3) Nelson, D. R., Koymans, L., Kamataki, T., Stegeman, J. J., Feyereisen, R., Waxman, D. J., Waterman, M. R., Gotoh, O., Coon, M. J., Estabrook, R. W., Gunsalus, I. C. and Nebert, D. W.: P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics, 6: 1–42 (1996). 4) Xu, G., Salen, G., Shefer, S., Ness, G. C., Chen, T. S., Zhao, Z. and Tint, G. S.: Reproducing abnormal cholesterol biosynthesis as seen in the Smith­Lemli­ Opitz syndrome by inhibiting the conversion of 7­ dehydrocholesterol to cholesterol in rats. J. Clin. In­ vest, 95: 76–81 (1995). 5) White, P. C.: Steroid 11 b­hydroxylase deˆciency and related disorders. Endocrinol Metab Clin. North Am, 30: 61–79 (2001). 6) Lee, H.: CYP21 mutations and congenital adrenal hyperplasia. Clin. Genet., 59: 293–301 (2001). 7) Nebert, D. W., Nelson, D. R., Adesnik, M., Coon, M. J., Estabrook, R. W., Gonzalez, F. J., Guengerich, F. P., Gunsalus, I. C., Johnson, E. F., Kemper, B., Levin, W., Phillips, I. R., Sato, R. and Waterman, M. R.: The P450 superfamily: updated listing of all genes and recommended nomenclature for the chromosomal loci. DNA, 8: 1–13 (1989). 8) Lawton, M. P., Cashman, J. R., Cresteil, T., Dolphin, C. T., Elfarra, A. A., Hines, R. N., Hodgson, E., Kimura, T., Ozols, J., Phillips, I. R., Philpot, R. M., Poulsen, L. L., Rettie, A. E., Shephard, E. A., Williiams, D. E. and Ziegler, D. M.: A nomenclature for the mammalian ‰avin­containing monooxygenase gene family based on amino acid sequence identities. Arch. Biochem. Biophys., 308: 254–257 (1994). 9) Vatsis, K. P., Weber, W. W., Bell, D. A., Dupret, J. M., Evans, D. A., Grant, D. M., Hein, D. W., Lin, H. J., Meyer, U. A., Relling, M. V., Sim, E., Suzuki, T. and Yamazoe, Y.: Nomenclature for N­acetyltran­ sferases. Pharmacogenetics, 5: 1–17 (1995). 10) Beetham, J. K., Grant, D., Arand, M., Garbarino, J., Kiyosue, T., Pinot, F., Oesch, F., Belknap, W. R., Shinozaki, K. and Hammock, B. D.: Gene evolution of epoxide hydrolases and recommended nomenclature. DNA Cell Biol., 14: 61–71 (1995). 11) Meyer, U. A.: Genetic polymorphisms of drug metabolism. Fundam Clin. Pharmacol., 4: 595–615 (1990). 12) Nebert, D. W., Adesnik, M., Coon, M. J., Estabrook, R. W., Gonzalez, F. J., Guengerich, F. P., Gunsalus, I. C., Johnson, E. F., Kemper, B., Levin, W., Phillips, I.

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Genetic Polymorphism of Human P450

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