Colorectal cancer and genetic polymorphisms of CYP1A1, GSTM1 and GSTT1: A case‐control study in the Grampian region of Scotland

Abstract

Cytochrome P-450 CYP1A1 is involved in the metabolism of polycyclic aromatic hydrocarbons (PAHs) that are derived from meat intake and tobacco smoking. Expression of the CYP1A1 gene is induced by compounds present in cruciferous vegetables. The glutathione S-transferases play a central role in the detoxification of carcinogens, including PAHs. We investigated the association between colorectal cancer and three variants (CYP1A1*2A, CYP1A1*2C, CYP1A1*4) of the CYP1A1 gene, and homozygosity for the null deletion of the GSTM1 and GSTT1 genes, and the joint effects of these genotypes and smoking, meat intake and intake of green leafy vegetables in a population-based study of 264 cases and 408 controls in Northeast Scotland. There was an inverse association with the CYP1A1*4 (m4) variant (OR 0.3, 95% CI 0.13-0.70). The OR for the CYP1A1*2C (m2) variant was 1.3 (95% CI 0.59-2.91), which is similar to a combined estimate for previous studies (OR 1.2, 95% CI 0.95-1.41). We observed no association with the CYP1A1*2A (m1) variant, or the GSTM1 and GSTT1 polymorphisms. Significant interactions between all 3 CYP1A1 variants and meat intake, and between the m1 and m2 variants and intake of green leafy vegetables, were observed. There was no evidence of interaction between CYP1A1 and smoking, and no evidence of interaction between the GSTM1 or GSTT1 polymorphisms and smoking, meat intake, green leafy vegetable intake, CYP1A1 variants or each other. ' 2006 Wiley-Liss, Inc.Key words: colorectal neoplasms; cytochrome P-450 CYP1A1; GSTM1 protein; glutathione S-transferase T1; polymorphism Evidence on the association between colorectal cancer and consumption of cooked meats, 1 tobacco smoking 2,3 and vegetable intake, 4-6 all of which are modifiable exposures with a potentially major public health impact, is inconsistent. Randomized trials 7,8 have confirmed evidence from most observational studies, [9][10][11][12] indicating an inverse relation between postmenopausal oestrogen replacement therapy and colorectal cancer, but considerable heterogeneity in the magnitude of this association was apparent. It is possible that these inconsistencies are in part due to differences between populations in the frequency of variants of genes, whose products modulate the effects of these exposures.A possible unifying factor underlying exposure to cooked meats, tobacco smoke and postmenopausal oestrogen replacement therapy is the presence of polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines. Cooking of meat and fish results in the formation of PAHs and, particularly at high temperatures, heterocyclic amines, which are carcinogenic in animals. [13][14][15] Tobacco smoking is another source of PAH exposure.16 PAHs affect oestrogen production and metabolism. 17CYP1A1 is expressed in the large bowel. 18,19 Because of the involvement of CYP1A1 in the metabolism of PAHs and oestrogens, and perhaps cruciferous vegetables and heterocyclic amines [20][21][22][23][24][25] (Table I), it might be expected that CYP1A1 variants might influence t...

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

“…Other studies do not support this fi nding (45). Most investigations on cancer risk arising from CYP1A1 polymorphism have studied the effects of modifi ed CYP1A1 in association with defi cient phase II enzymes (predominantly GST) and other gene variants that affect activation and detoxification of CYP1A1 substrates (46). GST detoxifi es many of activated carcinogens that are produced during the Phase I metabolism.…”

Association between polymorphisms in the biometabolism genes CYP1A1, GSTM1, GSTT1 and GSTP1 in bladder cancer

“…The biological consequences of defects in the expression of GSTM1, GSTT1 and GSTP1 include susceptibility to skin, lung, colon and bladder cancer [18][19][20][21].…”

An Updated Pooled Analysis of Glutathione S-transferase Genotype Polymorphisms and Risk of Adult Gliomas

“…In addition, these enzymes are thought to play a role in protecting DNA from oxidative damage (Little et al, 2006). Based on their sequence homology and immunological cross-reactivity, human cytosolic GSTs have been grouped into several families; the most frequently mentioned are designated as GST-Mu (GSTM), GST-Theta (GSTT) and GST-Pi (GSTP) (Hashibe et al, 2003;Egan et al, 2004;Nebert and Vasiliou, 2004).…”