Effect of glutathione-S-transferase polymorphisms on the cancer preventive potential of isothiocyanates: An epidemiological perspective

Mutation Research 592 (2005) 58–67

Effect of glutathione-S-transferase polymorphisms on the cancer preventive potential of isothiocyanates: An epidemiological perspective Adeline Seow a,∗ , Harri Vainio b , Mimi C. Yu c a

Department of Community, Occupational and Family Medicine, National University of Singapore, 16 Medical Drive, MD3, Singapore 117597, Singapore b Finnish Institute of Occupational Health, Topeliuksenkatu 41 a A, FIN-00250 Helsinki, Finland c University of Minnesota Cancer Center, Minneapolis, MN 55455, USA Available online 12 July 2005

Abstract Isothiocyanates (ITCs) are widely distributed in cruciferous vegetables and are biologically active against chemical carcinogenesis due to their ability to induce phase II conjugating enzymes. Among these is the glutathione-S-transferase (GST) family of enzymes, which in turn catalyzes the metabolism of ITCs, for which it has high substrate specificity. A recent body of epidemiologic data on the inverse association between cruciferous vegetable/ITC intake and cancers of the colo-rectum, lung and breast, also support that this protective effect is greater among individuals who possess the GSTM1 or T1 null genotype, and who would be expected to accumulate higher levels of ITC at the target tissue level, a pre-requisite for their enzyme-inducing effects. The association between ITC and cancer, and its modification by GST status, is most consistent for lung cancer and appears to be strongest among current smokers. Within limits, a comparison between groups which have been stratified by GST genotype may be less susceptible to confounding by other variables, given the random assortment of genes in gametogenesis. While a more complete understanding of the overall effects on health will need to take into account other components such as indoles and anti-oxidants, the interaction between ITC intake and GST genotype may provide a firmer basis to support a biologically significant role for ITC in cruciferous vegetables. © 2005 Elsevier B.V. All rights reserved. Keywords: Cruciferous vegetables; Gene–diet interaction; Phase II metabolizing enzymes; Genetic polymorphisms

1. Introduction Diet is a complex mixture that includes not only the major nutrients and micronutrients but also ∗

Corresponding author. Tel.: +65 68744974; fax: +65 67791489. E-mail address: [email protected] (A. Seow).

0027-5107/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.mrfmmm.2005.06.004

non-nutrient compounds which may exert important biological effects [1]. In addition, other chemicals which may be incorporated during cultivation, processing or cooking of food may also influence disease risk. The full extent of biologically active components in our diet, and the pathways involved in their action, is incompletely understood. There has been recent inter-

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est in applying a growing understanding of genomics to the study of diet–disease relationships, and a recognition that this approach may help to clarify mechanisms in the area of diet and cancer prevention [2,3].

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induce both phase I and phase II enzymes and to a lesser extent, may directly inhibit phase I enzymes [24,25]. Based on in vitro studies, ITCs are also believed to confer protection against cancer by stimulating apoptosis, through a mechanism distinct from its role in carcinogen metabolism [26,27].

2. Brassica, isothiocyanates and cancer risk Isothiocyanates (ITCs) are non-nutrient bioactive compounds which are widely distributed in cruciferous vegetables (Brassica), such as broccoli, cabbage, kale, Brussels sprouts, watercress and mustard. They occur in intact plants as glucosinolates. The alkyl and aralkyl glucosinolates (e.g. gluconasturtiin and glucoraphanin/sulphoraphane) undergo hydrolysis by myrosinase in plant cells or gut bacteria to release isothiocyanates. Indoyl glucosinolates are converted by the same mechanism to indole-3-carbinol (I-3-C) [4]. There is substantial epidemiologic evidence of an inverse association between consumption of Brassica vegetables and risk of cancer, most consistently for the lung, stomach, colon and rectum [5]. Most early studies measured exposure by eliciting frequency of intake of individual vegetables, or by summing up intake for several members of this class of compounds. More recently, attempts have been made to account for varying levels of ITC in different vegetables by incorporating measured ITC concentrations with food frequency questionnaire data [6–8]. The development and validation of urinary total ITC as a biomarker of exposure [9,10] has provided a tool to further clarify ITC–disease associations in epidemiologic studies [11,12]. ITCs are believed to exert their chemoprotective effect by modulating biotransformation enzyme pathways, primarily through inducing phase II enzymes [13–15], thereby enhancing the elimination of activated carcinogens. This capacity has been demonstrated experimentally via the ability of these compounds to block benzo[a]pyrene-induced damage [16] and 4-(methylnitrosoamine)-1-(3-pyridyl)-1-butanone (NNK)-induced tumorigenesis [17,18], reduce formation of colonic aberrant crypt foci in rats [19] and modulate heterocyclic amine metabolism in humans [20,21]. In vitro evidence suggests that the potency of the phase II enzyme induction effects of ITC may be a function of the level of intracellular accumulation over time [22,23]. Some ITCs induce phase I enzymes, others

3. The role of glutathione-S-transferase in ITC metabolism The glutathione-S-transferase (GST) family is a major group of phase II detoxifying enzymes which conjugates glutathione (GSH) with compounds containing an electrophilic centre. GST isoenzymes, of which GSTM1 and T1 have been most extensively studied, demonstrate a very broad substrate specificity, including metabolites of aflatoxin B1 , benzo[a]pyrene, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), dichlorodiphenyltrichloroethane (DDT), chemotherapeutic agents such as cyclophosphamide, as well as products of oxidative stress [28]. Consumption of Brassica vegetables enhances GST activity in humans [29–31], via the antioxidant response element (ARE), through a pathway which involves the NF-E2-related factor-2 (NRf2) and increases synthesis of GST [25]. Importantly, GST also catalyzes the conjugation of glutathione to isothiocyanates, and ITCs are among the substrates most rapidly conjugated by GST [32]. While this reaction is reversible, enzyme kinetics suggest that the equilibrium strongly favours conjugation [33]. This pathway leads to the formation of N-acetylcysteine conjugates (dithiocarbamates) which are subsequently excreted by the kidneys [33,34]. In humans, genes coding for the major GST isoenzymes have been identified, and polymorphisms at these loci characterized. The homozygous deletion of GSTM1 gives rise to the null phenotype in which there is no expression of the GSTM1 protein, whereas in other cases (e.g. GSTP1) the polymorphism may result in a low activity allele [35]. The prevalence of the null genotype varies between ethnic groups from 27 to 53% for GSTM1 and 20 to 47% for GSTT1 [36]. Numerous epidemiologic studies have examined the effect of GSTM1 and T1 deletions on cancer risk. Recent pooled analyses report an odds ratio of 1.08 (95% CI 0.98–1.18) for lung cancer [37]; for breast cancer, the pooled estimates were 0.98 (0.86–1.12) associated with

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the GSTM1 null genotype and 1.11 (0.87–1.41) for the GSTT1 null genotype [38]. Based on our understanding of the biological interaction between GST and ITCs, we would expect that individuals who are null for GST and who therefore less readily conjugate and excrete these compounds, would have greater amounts of ITC at the tissue level, and hence would experience a greater protective effect. One important line of evidence that this is indeed the case would be if well-conducted epidemiologic studies bear out the abrogation of protective effects of ITC in GST non-null, relative to null, individuals. In addition, this would strengthen the evidence that ITCs are a major chemopreventive component of cruciferous vegetables, and enhance our understanding of the factors which influence their impact at the cellular level.

4. Epidemiological studies on ITC, GST and cancer risk To date, there have been two prospective and eight case–control studies which have specifically examined the interaction between ITC, GST and risk of cancer or precursor lesions (Table 1). 4.1. Lung The organ site for which most epidemiologic data is available in this regard is the lung. This is particularly relevant in the light of the epidemiologic and experimental evidence supporting a plausible mechanism for the effect of ITC on smoking-associated cancers [39–41]. In animal studies, phenethyl ITC inhibits lung tumorigenesis by NNK, a tobacco-associated carcinogen [18,42]. Similarly, human studies support a stronger effect for ITC in smokers. In a nested case–control study within a prospective cohort of Chinese men, London et al. [11] reported that having detectable levels of urinary ITC at baseline was inversely related with subsequent lung cancer risk, primarily among those who were GSTM1 null or GSTT1 null. The largest effect was noted among those who possessed the combined M1 and T1 null genotypes. This was the first epidemiologic study to directly demonstrate a link between a biomarker of ITC intake and a cancer outcome, and was con-

ducted in a population in which 81.5% of cases and 47.5% of controls were current smokers. In a US population-based case–control study, a similar pattern was observed with GSTT1 among current, and to a smaller extent among former smokers [8]. We and others subsequently showed that a similar effect could be demonstrated in lifetime non-smokers [6,43], although the magnitude of the ITC effect and the difference between individuals null and non-null for GST was less marked than among smokers [6]. 4.2. Colon/rectum The colon is another site where the protective effect of fruit and vegetables has been consistently observed [39,44]. In a case–control study of colon cancer [45] a protective effect of cruciferous vegetable consumption was observed, but only among those diagnosed at a young age (<55 years), and this effect was greater among GSTM1 null individuals than among non-null individuals. The authors suggested that the lack of effect among older persons may be due to differences in the types and composition of cruciferae consumed by older and younger persons, or to changes in gut physiology or detoxification potential of GST with age. Among participants of the Singapore Chinese Health Study, a population with high consumption of cruciferae, there was a significant effect of dietary ITC only among individuals who were null for both GSTM1 and GSTT1 (OR 0.4, 0.2–1.0) [7]. The findings for colon cancer are consistent with earlier data showing the same effect with colorectal adenomas. In 1998, Lin et al. [46] reported that among asymptomatic subjects undergoing screening sigmoidoscopy, intake of broccoli was significantly associated with lower risk of colorectal adenomas overall, but when examined by genotype, only subjects null for GSTM1 experienced the protective effect. The authors later followed up this report with data showing a lack of effect of GSTT1, but a significant effect among individuals null for GSTT1 and/or GSTM1 which was absent in non-null individuals [47]. 4.3. Breast To date, there is limited data on the GST–ITC relationship in the breast. Fowke et al. [12] compared urinary ITC levels at diagnosis among breast cancer

Table 1 Epidemiologic studies of cruciferous vegetable/isothiocyanate intake, glutathione-S-transferase genotype and cancer risk Reference

Study population

Type of study/number of cases and controls

Type of cancer

Exposure

Risk estimate for effect of ITC exposure by GST genotype

London et al. [11]

Chinese men and women (Shanghai, China)

Prospective; nested case–control, 232 cases, 710 matched controls

Lung

Urinary ITC (detectable vs. non-detectable)

GSTM1

US men and women

Case–control study; 503 cases, 465 controls

Lung

Dietary ITC intake (≤ vs. >median)

Either Both GSTM1 GSTT1

Zhao et al. [6]

Lewis et al. [43] Slattery et al. [45]

Seow et al. [7]

Singapore Chinese women

Multi-centre in Europe and South America US men and women

Chinese men and women (Singapore Chinese Health Study)

Case–control study, 233 cases, 187 hospital controls

Lung

Case–control study; 122 cases and 123 controls.

Lung

Case–control; 1579 cases, 1898 population controls

Colon cancer

Prospective; nested case–control, 213 cases, 1197 controls

Dietary ITC intake (> vs. ≤median)

GSTM1 GSTT1

Dietary cruciferous vegetable intake (high vs. low) Cruciferous vegetable intake

Colorectal Dietary ITC (> vs.
GSTM1

GSTM1

GSTM1 GSTT1 Either Both

1.2 (0.7–2.2) 0.4 (0.2–0.6) 1.0 (0.5–1.8) 0.5 (0.3–0.9) 1.0 (0.6–1.7) 0.3 (0.1–0.6) 2.1 (low vs. high) 1.4 (low vs. high) 1.7 (low vs. high) 2.4 (low vs. high) 0.8 (0.4–1.6) 0.6 (0.3–0.9) 0.8 (0.4–1.4) 0.5 (0.3–1.0) 0.7 (0.2–2.7) 0.3 (0.1–1.3)

Null/nonconsumer Non-null/>4 servings per week Null/>4 servings per week Non-null Null Non-null Null Non-null Null

Ref. 0.4 (0.2–1.0)

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Spitz et al. [8]

GSTT1

Non-null Null Non-null Null Non-null Null Non-null Null Non-null Null Non-null Null Non-null Null Non-null Null

0.2 (0.1–0.5) 0.7 (0.5–1.1) 0.9 (0.5–1.4) 1.0 (0.6–1.5) 0.6 (0.4–1.1) 0.9 (0.6–1.3) 0.4 (0.2–1.0)

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Table 1 (Continued ) Reference

Study population

Lin et al. [46,47]

US Kaiser Case–control; 457 cases, Permanante screening 505 matched controls attenders

Chinese women (Shanghai Breast Cancer Study)

Case–control study, 337 case-population control pairs

Type of cancer

Exposure

Risk estimate for effect of ITC exposure by GST genotype

Colorectal adenomas detected on sigmoidoscopy

Cruciferous vegetable intake (>1 vs. 0 serves/week)

GSTM1

Breast

Urinary ITC (Q4 vs. Q1)

GSTT1 Both Either GSTM1 GSTT1 GSTP1

Ambrosone US women (Western Case–control study, 697 et al. New York Diet Study) cases, 810 community [48] controls

Breast

Broccoli intake (highest vs. lowest tertile)

Pre-menopausal GSTM1 GSTT1 Post-menopausal GSTM1 GSTT1

Gaudet et al. [52]

US men and women

Case–control study, 149 cases and 180 hospital controls

Squamous cell Cruciferous vegetable cancers of the head intake (consumers vs. and neck (oral cavity, non-consumers) pharynx, larynx)

GSTM1

GSTT1

Non-null Null Non-null Null Non-null Null Non-null Null Non-null Null AA AG/GG Non-null Null Non-null Null Non-null Null Non-null Null Null/consumers vs. Non-null/ non-consumers Null/consumers vs. Non-null/ non-consumers

1.0 (0.7–1.1) 0.5 (0.3–0.9) 0.9 (0.5–1.6) 0.9 (0.4–2.0) 0.9 (0.5–1.5) 0.6 (0.3–0.9) 0.6 (0.3–1.4) 0.5 (0.2–0.9) 0.6 (0.3–1.3) 0.4 (0.2–0.9) 0.6 (0.4–1.3) 0.5 (0.2–1.2) 0.7 (0.1–1.2) 1.0 (0.4–3.1) 0.7 (0.3–1.8) 0.3 (0.1–1.6) 1.0 (0.4–3.0) 0.5 (0.2–1.5) 0.7 (0.3–1.7) 2.1 (0.5–9.7) 1.1 (0.2–5.4)

2.2 (0.6–8.8)

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Fowke et al. [12]

Type of study/number of cases and controls

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cases with levels among matched population controls in Shanghai, China. High urinary ITC, but not selfreported dietary intake of cruciferae, conferred a 50% reduction in risk among pre-menopausal women but the relationship was less clear among post-menopausal subjects. The trend was stronger and statistically significant among GSTM1 null individuals, and among GSTT1 null individuals. More recently, investigators reported a reduction in breast cancer risk of between 20 and 30% with high intake of cruciferous vegetables in the Western New York Diet Study [48], which appeared confined to pre-menopausal women. Among a subset of participants who provided blood specimens, the effect of GST genotype was inconsistent between pre- and post-menopausal women and between GSTM1 and T1 status. The largest inverse associations were observed among pre-menopausal women null for GSTT1, and post-menopausal women null for GSTM1; but none of these were significant due to small numbers. Given the hormone responsiveness of this target organ, and the possible role of indoles, which are also constituents of Brassica vegetables, in hormone-related pathways [49], interpreting an effect of GST–ITC in this target organ may be more complex, and further studies which incorporate exposure to both ITCs and indoles will help to shed more light on this issue. 4.4. Other sites Tobacco carcinogens have been strongly associated with squamous cell carcinomas of the head and neck, and fruit and vegetable intake have also been shown to be protective for these sites [50,51]. To date, only one study, a hospital-based case control study [52], has examined the effect of GST and ITC on head and neck cancer risk. There was a suggestion of a protective effect of fruit and raw, but not cooked, vegetable intake, but precision of the estimates was limited by sample size. There was no evidence of a protective effect of cruciferous vegetables, alone or when stratified by GST genotype. 4.5. Summary Overall, the results of epidemiologic studies to date are clearest in support of a GST–ITC effect in the lung, with more limited evidence in the colon, which is

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consistent with what is known from experimental data about the relative potency of ITC against carcinogens which are believed to be relevant to these organ sites [16–21]. For the lung, this is further evidenced by relationships being more marked among smokers than exor never smokers.

5. Single nucleotide polymorphisms as ‘randomizers’ The classic case–control design, with unrelated controls drawn from the source population or from hospital patients, has been the most common epidemiologic approach to examining gene–environment interactions [53]. This design enables investigators to estimate the odds ratios associated with the main effects, and to detect interaction either as a departure from a multiplicative or from an additive model [54]. The latter has been described as more appropriate for biological interactions in which both factors participate in the same pathway [55,56]. One important element in this approach is that the sample size required to achieve adequate power to detect these interactions is large, in the range of 1500–5000 case–control pairs [54]. Another consideration in the interpretation of exposure–disease associations from these studies is the extent to which confounding by variables related both to the outcome and to the exposures of interest, have been adequately dealt with [57]. This is particularly relevant when dealing with exposures which are likely to be linked with other risk factors, e.g. diet and lifestyle. Smith and Ebrahim [58] suggest that in studying gene–environment relationships, it is possible to apply Mendel’s second law to addressing the problem of confounding. This ‘law of random assortment’, when condensed, states that ‘the inheritance of one trait is independent of the inheritance of other traits’. In other words, a single nucleotide polymorphism which classifies individuals into genotype-groups (e.g. GST null and non-null) effectively ‘randomizes’ these individuals with regard to all other traits that may be known or unknown confounders of the exposure–disease (e.g. ITC–cancer) relationship. If this is true, then if we observe a statistical relationship that mirrors the putative biological link between genotype and dietary exposure (in this case, if the ITC–cancer relationship

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6. Cruciferous vegetables as complex mixtures

Fig. 1. Stratification by GST genotype as a means of understanding the ITC–cancer relationship. 1 Assuming that the null and non-null genotypes are distributed independently of potential confounders (Smith and Ebrahim, 2003).

is consistently stronger among GST null individuals), then this may be considered as support for an actual involvement of ITC in the aetiologic pathway (Fig. 1). Clearly, there are limitations to adopting this approach, and the possibility of linkage disequilibrium with other relevant polymorphisms, or the ‘buffering’ effects by other genes to compensate for lack of function should be given serious consideration [58]. In addition, the biological model in which the gene and environmental exposure are thought to interact may determine how confounding factors are defined [59]. For example, genetic polymorphisms which affect enzyme inducibility may not reduce the problem of confounding by exposures which also induce these enzymes. However, there is emerging data to show that, within these limitations, genotype may be reasonably independent of other variables. Specifically, a recent study showed that smoking behaviour was not associated with CYP1A1, GSTM1, GSTT1, NAT2 and GSTP1 genotype among control subjects from several different populations [60], and our own data suggest that individuals who differ by GSTM1 and T1 genotype are similar in diverse characteristics such as age at menarche, first birth and even family history of cancer (Seow et al., unpublished data).

The chemoprotective effects of fruit and vegetable are likely to derive from various components, including anti-oxidant activity [24,61,62] among others. It is important to note that cruciferous vegetables vary in their indole and ITC composition [63]. Animal data suggests that indole-3-carbinol administration leads to a lowering of urinary levels of NNK metabolites and inhibition of lung tumorigenesis [64]; the same effect on NNK excretion has been observed in humans [65]. Hence, while our understanding of the biological relationship between GST and ITC and its consistency with the epidemiologic data reviewed here support a role for ITCs as chemopreventive agents in cruciferae, it is important to consider the specificity of both indole and ITC effects in interpreting data from epidemiologic studies, depending on the target organ and the putative carcinogenic pathway. The ability of some isothiocyanates to induce phase I enzymes (such as cytochrome P450 (CYP)) as well as phase II enzymes, has implications on the overall effect of these compounds, since induction of CYP may increase activation of a number of carcinogens such as polyaromatic hydrocarbons. Other possible harmful effects of cruciferae have been investigated, and there is suggestion from experimental studies that application of specific ITCs may have a clastogenic effect in vitro [66,67], and increase the formation of reactive oxygen species [68,69]. It is likely that the balance between anti-oxidant and pro-oxidant activities depends on several factors such as the composition and concentration of glucosinolates, concomitant exposure to genotoxic agents, and the target organ. These findings argue against dietary supplementation or the use of high levels of ITC as a potential chemopreventive, till a more complete understanding of their effects is obtained.

7. Conclusion The role of cruciferous vegetables as cancer chemopreventives draws support from a large body of experimental and epidemiologic data. It is also clear that isothiocyanates, which are a major component, have biological properties that act to reduce carcinogeninduced DNA damage. On balance, epidemiologic

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studies demonstrate the modification of ITC effects by GST, particularly in the lung and colon, which can be predicted based on the metabolic pathway. Taken together, this evidence supports a biological role for ITC in preventing cancer, and underlines the benefit of including cruciferous vegetables as part of a balanced diet.

[12]

[13]

[14]

Acknowledgement [15]

The author would like to thank Dr. Paul Brennan for helpful discussions on this topic. [16]

References [1] T.J. Key, N.E. Allen, E.A. Spencer, R.C. Travis, The effect of diet on risk of cancer, Lancet 360 (2002) 861–868. [2] B.N. Ames, Cancer prevention and diet: help from single nucleotide polymorphisms, PNAS 96 (1999) 12216–12218. [3] R. Elliott, T.J. Ong, Nutr. Genom., BMJ 324 (2002) 1438–1442. [4] G.S. Stoewsand, Bioactive organosulfur phytochemicals in Brassica oleracea vegetables—a review, Fd. Chem. Toxicol. 33 (1995) 537–543. [5] D.T.H. Verhoeven, R.A. Goldbohm, G. van Poppel, H. Verhagen, P.A. van den Brandt, Epidemiological studies on brassica vegetables and cancer risk, Cancer Epidemiol. Biomark. Prev. 5 (1996) 733–748. [6] B. Zhao, A. Seow, E.J.D. Lee, W.T. Poh, M. Teh, P. Eng, Y.T. Wang, W.C. Tan, M.C. Yu, H.P. Lee, Dietary isothiocyanates, glutathione-S-transferase -M1, -T1 polymorphisms and lung cancer risk among Chinese women in Singapore, Cancer Epidemiol. Biomark. Prev. 10 (2001) 1063–1067. [7] A. Seow, J.M. Yuan, C.L. Sun, D. Van Den Berg, H.P. Lee, M.C. Yu, Dietary isothiocyanates, glutathione-S-transferase polymorphisms and colorectal cancer risk in the Singapore Chinese Health Study, Carcinogenesis 23 (2002) 2055–2061. [8] M.R. Spitz, C.M. Duphorne, M.A. Detry, P.C. Pillow, C.I. Amos, L. Lei, M. de Andrade, X. Gu, W.K. Hong, X. Wu, Dietary intake of isothiocyanates: evidence of a joint effect with glutathione-S-transferase polymorphisms in lung cancer risk, Cancer Epidemiol. Biomark. Prev. 9 (2000) 1017–1020. [9] F.L. Chung, D. Jiao, S.M. Getahun, M.C. Yu, A urinary biomarker for uptake of dietary isothiocyanates in humans, Cancer Epidemiol. Biomark. Prev. 7 (1998) 103–108. [10] A. Seow, C.Y. Shi, F.L. Chung, D. Jiao, J.H. Hankin, H.P. Lee, G.A. Coetzee, M.C. Yu, Urinary total isothiocyanate (ITC) in a population-based sample of middle-aged and older Chinese in Singapore: relationship with dietary total ITC and glutathione-S-transferase M1/T1/P1 genotypes, Cancer Epidemiol. Biomark. Prev. 7 (1998) 775–781. [11] S.J. London, J.M. Yuan, F.L. Chung, Y.-T. Gao, G.A. Coetzee, R.K. Ross, M.C. Yu, Isothiocyanates, glutathione-S-transferase

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

65

M1 and T1 polymorphisms, and lung-cancer risk: a prospective study of men in Shanghai, China, Lancet 356 (2000) 724–729. J.H. Fowke, F.L. Chung, F. Jin, D. Qi, Q. Cai, C. Conaway, J.R. Cheng, X.O. Shu, Y.T. Gao, W. Zheng, Urinary isothiocyanate levels, brassica and human breast cancer, Cancer Res. 63 (2003) 3980–3986. Y. Zhang, P. Talalay, Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms, Cancer Res. 54 (Suppl.) (1995) 1976s–1981s. P. Talalay, J.D. Fahey, Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolism, J. Nutr. 11 (2001) 3027S–3033S. P. Rose, K. Faulkner, G. Williamson, R. Mithen, 7Methylsulfinylheptyl and 8-methylsulfinyloctyl isothiocyanates from watercress are potent inducers of phase II enzymes, Carcinogenesis 21 (2000) 1983–1988. B. Laky, S. Knasmuller, R. Gminski, V. Mersch-Sundermann, G. Scharf, R. Verkerk, C. Freywald, M. Uhl, F. Kassie, Protective effects of Brussels sprouts towards B[a]P-ionduced DNA damage: a model study with the single-cell gel electrophoresis (SCGE)/Hep G2 assay, Fd. Chem. Toxicol. 40 (2002) 1077–1083. Z. Guo, T.J. Smith, E. Wang, N. Sadrieh, Q. Ma, P.E. Thomas, C.S. Yang, Effects of phenethyl isothiocyanate, a carcinogenesis inhibitor, on xenobiotic-metabolizing enzymes and nitrosamine metabolism in rats, Carcinogenesis 13 (1992) 2205–2210. S.S. Hecht, N. Trushin, J. Rigotty, S.G. Carmella, A. Borukhova, S. Akerkar, A. Rivenson, Complete inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced rat lung tumorigenesis and favorable modification of biomarkers by phenethyl isothiocyanate, Cancer Epidemiol. Biomark. Prev. 5 (1996) 645–652. F.L. Chung, C.C. Conaway, C.V. Rao, B.S. Reddy, Chemoprevention of colonic aberrant crypt foci in Fischer rats by sulforaphane and phenethyl isothiocyanate, Carcinogenesis 21 (2000) 2287–2291. S. Murray, B.G. Lake, S. Gray, A.J. Edwards, C. Springall, E.A. Bowey, G. Williamson, A.R. Boobis, N.J. Gooderham, Effect of cruciferous vegetable consumption on heterocyclic aromatic amine metabolism in man, Carcinogenesis 22 (2001) 1413–1420. D.G. Walters, P.J. Young, C. Agus, M.G. Knize, A.R. Boobis, N.J. Gooderham, B.G. Lake, Cruciferous vegetable consumption alters the metabolism of the dietary carcinogen 2-amino1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in humans, Carcinogenesis 25 (2004) 1659–1669. Y. Zhang, P. Talalay, Mechanism of differential potencies of isothiocyanates as inducers of anticarcinogenic phase 2 enzymes, Cancer Res. 58 (1998) 4632–4639. L. Ye, Y. Zhang, Total intracellular accumulation levels of dietary isothiocyanates determine their activity in elevation of cellular glutathione and induction of Phase 2 detoxification enzymes, Carcinogenesis 22 (2001) 1987–1992. D.T.H. Verhoeven, H. Verhagen, R.A. Goldbohm, P.A. van den Brandt, G. van Poppel, A review of mechanisms underlying anticarcinogenecity by brassica vegetables, Chem. Biol. Interact. 103 (1997) 79–129.

66

A. Seow et al. / Mutation Research 592 (2005) 58–67

[25] J.W. Lampe, S. Peterson, Brassica, biotransformation and cancer risk: genetic polymorphisms alter the preventive effects of cruciferous vegetables, J. Nutr. 132 (2002) 2991–2994. [26] C. Bonnesen, I.M. Eggleston, J.D. Hayes, Dietary indoles and isothiocynates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines, Cancer Res. 61 (2001) 6120–6130. [27] R. Yu, S. Mandlekar, K.J. Harvey, D.S. Ucker, A.N.T. Kong, Chemopreventive isothiocyanates induce apoptosis and caspase-3-like protease activity, Cancer Res. 58 (1998) 402–408. [28] J.D. Hayes, D.J. Pulford, The glutathione-S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance, Crit. Rev. Biochem. Mol. Biol. 30 (1995) 445–600. [29] J.W. Lampe, C. Chen, S. Li, J. Prunty, M.T. Grate, D.E. Meehan, K.V. Barale, D.A. Dightman, Z. Feng, J.D. Potter, Modulation of human glutathione-S-transferases by botanically defined vegetable diets, Cancer Epidemiol. Biomark. Prev. 9 (2000) 787–793. [30] W.A. Nijhoff, t.P.J. Mulder, H. Verhagen, G. van Poppel, W.H.M. Peters, Effects of consumption of Brussels sprouts on plasma and urinary glutathione-S-transferase class-␣ and -␲ in humans, Carcinogenesis 16 (1995) 955–957. [31] W.A. Nijhoff, M.J.A.L. Grubben, F.M. Nagengast, J.B.M.J. Jansen, H. Verhagen, G. van Poppel, W.H.M. Peters, Effects of consumption of Brussels sprouts on intestinal and lymphocytic glutathione-S-transferases in humans, Carcinogenesis 16 (1995) 2125–2128. [32] R.H. Kolm, U.H. Danielson, Y. Zhang, P. Talalay, B. Mannervik, Isothiocyanates as substrates for human glutathione transferases: structure–activity studies, Biochem. J. 311 (1995) 453–459. [33] Y. Zhang, R.H. Kolm, B. Mannervik, P. Talalay, Reversible conjugation of isothiocyanates with glutathione catalysed by human glutathione transferases, Biochem. Biophys. Res. Commun. 206 (1995) 748–755. [34] T.A. Shapiro, J.W. Fahey, K.L. Wade, K.K. Stephenson, P. Talalay, Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables, Cancer Epidemiol. Biomark. Prev. 7 (1998) 1091– 1100. [35] R.C. Strange, A.A. Fryer, The glutathione-S-transferases: influence of polymorphism on cancer susceptibility, in: P. Vineis, N. Malats, M. Lang, A. d’Errico, N. Caporaso, J. Cuzick, P. Boffetta (Eds.), Metabolic Polymorphisms and Susceptibility to Cancer, IARC Scientific Publications No. 148, Lyon, 1999, pp. 231–250. [36] S. Garte, L. Gaspari, A.K. Alexandrie, C. Ambrosone, H. Autrup, J.L. Autrup, H. Baranova, L. Bathum, S. Benhamou, P. Boffetta, C. Bouchardy, K. Breskvar, J. Brockmoller, I. Cascorbi, M.L. Clapper, C. Coutelle, A. Daly, M. Dell-Omo, V. Dolzan, C.M. Dresler, A. Fryer, A. Haugen, D.W. Hein, A. Hildesheim, A. Hirvonene, L.L. Hsieh, M. Ingelman-Sundberg, I. Kalina, D. Kang, M. Kihara, C. Kiyohara, P. Kremers, P. Lazarus, L. Le Marchand, M.C. Lechner, E.M.M. van Lieshout,

[37]

[38]

[39]

[40]

[41] [42]

[43]

[44]

S. London, J.J. Manni, C.M. Maugard, S. Morita, V. NazarStewart, K. Noda, Y. Oda, F.F. Parl, R. Pastorelli, I. Persoon, W.H.M. Peters, A. Rannug, T. Rebbeck, A. Risch, L. Roelandt, M. Romkes, D. Ryberg, J. Salagovic, B. Schoket, J. Seidegard, P.G. Shields, E. Sim, D. Sinnet, R.C. Strange, I. Stucker, H. Sugimura, J. To-Figuiras, P. Vineis, M.C. Yu, E. Taioli, Metabolic gene polymorphism frequencies in control populations, Cancer Epidemiol. Biomark. Prev. 10 (2001) 1239–1248. S. Benhamou, W.J. Lee, A.K. Alexandrie, P. Boffetta, C. Bouchardy, D. Butkiewics, J. Brockmoller, M.L. Clapper, A. Daly, V. Dolzan, J. Ford, L. Gaspari, A. Haugen, A. Hirvonen, K. Husgafvel-Pursiainen, M. Ingelman-Sundberg, I. Kalina, M. Kihara, P. Kremers, L. Le Marchand, S.J. London, V. NazarStewart, M. Onon-Kihara, A. Rannug, M. Romkes, D. Ryberg, J. Seidegard, P. Shields, R.C. Strange, I. Stucker, J. To-Figueras, P. Brennan, E. Taioli, Meta- and pooled analyses of the effects of glutathione-S-transferase M1 polymorphisms and smoking on lung cancer risk, Carcinogenesis 23 (2002) 1343–1350. F.D. Vogl, E. Taioli, C. Maugard, W. Zheng, L.F. Ribeiro Pinto, C. Ambrosone, F.F. Parl, V. Nedelcheva-Kristensen, T.R. Rebbeck, P. Brennan, P. Boffeta, Glutathione-S-transferases M1, T1, and P1 and breast cancer: a pooled analysis, Cancer Epidemiol. Biomark. Prev. 13 (2004) 1473–1479. D.T.H. Verhoeven, R.A. Goldbohm, G. van Poppel, H. Verhagen, P. van den Brandt, Epidemiological studies on brassica vegetables and cancer risk, Cancer Epidemiol. Biomark. Prev. 5 (1996) 733–748. S.S. Hecht, F.L. Chung, J.P. Richie Jr., S.A. Akerkar, A. Borukhova, L. Skowronski, S.G. Carmella, Effects of watercress consumption on metabolism of a tobacco-specific lung carcinogen in smokers, Cancer Epidemiol. Biomark. Prev. 4 (1995) 877–884. R.G. Ziegler, S.T. Mayne, C.A. Swanson, Nutrition and lung cancer, Cancer Causes Contr. 7 (1996) 157–177. Z. Guo, T.J. Smith, E. Wang, N. Sadrieh, Q. Ma, P.E. Thomas, C.S. Yang, Effeects of phenethyl isothiocyanate, a carcinogenesis inhibitor, on xenobiotic-metabolizing enzymes and nitrosamine metabolism in rats, Carcinogenesis (Lond.) 13 (1992) 2205–2210. S. Lewis, P. Brennan, F. Nyberg, W. Ahrens, V. Constatntinescu, A. Mukeria, S. Benhamou, H. Batura-Gabryel, I. BruskeHohlfeld, L. Simonato, A. Menezes, P. Boffetta, M.R. Re: Spitz, C.M. Duphonrne, M.A. Detry, P.C. Pillow, C.I. Amos, L. Lei, M. de Andrade, X. Gu, W.K. Hong, X. Wu, Dietary intake of isothiocyanates: evidence of a joint effect with glutathioneS-transferase polymorphisms in lung cancer risk, Cancer Epidemiol. Biomark. Prev. 9 (2000) 1018–1020 [Letter]; S. Lewis, P. Brennan, F. Nyberg, W. Ahrens, V. Constatntinescu, A. Mukeria, S. Benhamou, H. Batura-Gabryel, I. BruskeHohlfeld, L. Simonato, A. Menezes, P. Boffetta, M.R. Re: Spitz, C.M. Duphonrne, M.A. Detry, P.C. Pillow, C.I. Amos, L. Lei, M. de Andrade, X. Gu, W.K. Hong, X. Wu, Dietary intake of isothiocyanates: evidence of a joint effect with glutathioneS-transferase polymorphisms in lung cancer risk, Cancer Epidemiol. Biomark. Prev. 10 (2001) 1015–1016. J.D. Potter, Nutrition and colorectal cancer, Cancer Causes Contr. 7 (1996) 12–146.

A. Seow et al. / Mutation Research 592 (2005) 58–67 [45] M.L. Slattery, E. Kampman, W. Samowitz, B.J. Caan, J.D. Potter, Interplay between dietary inducers of GST and the GSTM-1 genotype in colon cancer, Int. J. Cancer 87 (2000) 728–733. [46] H.J. Lin, N.M. Probst-Hensch, A.D. Louie, I.H. Kau, J.S. Witte, S.A. Ingles, H.D. Frankl, E.R. Lee, R.W. Haile, Glutathione transferase null genotype, broccoli, and lower prevalence of colorectal adenomas, Cancer Epidemiol. Biomark. Prev. 7 (1998) 647–652. [47] H.J. Lin, H. Zhou, A. Dai, H.F. Huang, J.H. Lin, H.D. Frankl, E.R. Lee, R.W. Haile, Glutathione transferase GSTT1, broccoli, and prevalence of colorectal adnomas, Pharmacogenetics 12 (2002) 175–179. [48] C.B. Ambrosone, S.E. McCann, J.L. Freudenheim, J.R. Marshall, Y. Zhang, P.G. Shields, Breast cancer risk in premenopausal women is inversely associated with consumption of broccoli, a source of isothiocyanates, but is not modified by GST genotype, J. Nutr. 134 (2004) 1134–1138. [49] J.J. Michnovicz, H.L. Bradlow, Induction of estradiol metabolism by dietary indole-3-carbinol in humans, J. Natl. Cancer Inst. 82 (1990) 947–949. [50] K.A. Steinmetz, J.D. Potter, Vegetables, fruit and cancer. I. Epidemiology, Cancer Causes Contr. 2 (1991) 325–327. [51] B.W. Stewart, P. Kleihues (Eds.), World Cancer Report, IARC Press, Lyon, 2003. [52] M.M. Gaudet, A.F. Olshan, C. Pool, M.C. Weissler, M. Watson, D.A. Bell, Diet, GSTM1 and GSTT1 and head and neck cancer, Carcinogenesis 25 (2004) 735–740. [53] N. Andrieu, A.M. Goldstein, Epidemiologic and genetic approaches in the study of gene–environemnt interaction: an overview of available methods, Epidemiol. Rev. 20 (1998) 137–147. [54] P. Brennan, Gene–environment interaction and aetiology of cancer: what does it mean and how can we measure it? Carcinogenesis 23 (2002) 381–387. [55] C. Bonaiti-Pellie, Methodological aspects of investigating gene–nutrient interactions, Eur. J. Cancer Prev. 11 (2002) 69–74. [56] Q. Yang, M.J. Khoury, Evolving methods in genetic epidemiology. III. Gene–environment interactions in epidemiologic research, Epidemiol. Rev. 19 (1997) 33–43. [57] P. Vineis, A.J. McMichael, Bias and confounding in molecular epidemiological studies: special considerations, Carcinogenesis 19 (1998) 2063–2067. [58] G.D. Smith, S. Ebrahim, ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environ-

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

67

mental determinants of disease? Int. J. Epidemiol. 32 (2003) 1–22. E. Taioli, S. Garte, Covariates and confounding in epidemiologic studies using metabolic gene polymorphisms, Int. J. Cancer 100 (2002) 97–100. K.M. Smits, S. Benhamou, S. Garte, et al., Association of metabolic gene polymorphisms with tobacco consumption in healthy controls, Int. J. Cancer 110 (2004) 266–270. C. La Vecchia, A. Altieri, A. Tavani, Vegetables, fruit, antioxidants and cancer: a review of Italian studies, Eur. J. Nutr. 40 (2001) 261–267. J.H. Weisburger, Liestyle, health and disease prevention: the underlying mechanisms, Eur. J. Cancer Prev. 11 (Suppl. 2) (2002) S1–S7. S.S. Hecht, S.G. Carmella, P.M.J. Kenney, S.H. Low, K. Arakawa, M.C. Yu, Effects of cruciferous vegetable consumption on urinary metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in Singapore Chinese, Cancer Epidemiol. Biomark. Prev. 13 (2004) 997–1004. M.A. Morse, S.D. LaGreca, S.G. Amin, F.L. Chung, Effects of indole-3-carbinol on lung tumorigenesis and DNA methylation induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice, Cancer Res. 50 (1990) 2613–2617. E. Taioli, S. Garbers, H.L. Bradlow, S.G. Carmella, S. Akerkar, S.S. Hecht, Effects of indole-3-carbinol on the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in smokers, Cancer Epidemiol. Biomark. Prev. 6 (1997) 517–522. F. Kassie, S. Knasmuller, Genotoxic effects of allyl isothiocyanate (AITC) and phenethyl isothiocyanate (PEITC), Chemic-Biol. Interact. 127 (2000) 163–180. S.R.R. Musk, A.B. Astley, S.M. Edwards, P. Stephenson, R.B. Hubert, I.T. Johnson, Cytotoxic and clastogenic effects of benzyl isothiocyanate towards cultured mammalian cells, Fd. Chem. Toxicol. 33 (1995) 31–37. Y. Nakamura, H. Ohigashi, S. Masuda, A. Murakami, Y. Morimitsu, Y. Kawamoto, T. Osawa, M. Imagawa, K. Uchia, Redox regulation of glutathione-S-transferase induction by benzyl isothiocyanate: correlation of enzyme induction with the formation of reactive oxygen intermediates, Cancer Res. 60 (2000) 219–225. M. Sorensen, B.R. Jensen, H.E. Poulsen, X.S. Deng, N. Tygstrup, K. Dalhoff, S. Loft, Effects of a Brussels sprouts extract on oxidative DNA damage and metabolising enzymes in rat liver, Fd. Chem. Toxicol. 39 (2001) 533–540.