The effect of genetic polymorphisms in the vinyl chloride metabolic pathway on mutagenic risk.
Vinyl chloride (VC) is a human carcinogen known to undergo metabolism by cytochrome P450 2E1 (CYP2E1) to reactive intermediates that can cause oncogene and tumor suppressor gene mutations and that are further metabolized by acetaldehyde dehydrogenase (ALDH2) and glutathione-S-transferases (GSTs) to non-mutagenic end products. These metabolic enzymes have known polymorphisms that could lead to increased levels of the VC reactive intermediates and thus an increased risk for mutations and cancer following exposure. Using restriction fragment length polymorphism (RFLP) analysis, we have examined a cohort of 597 French VC workers for polymorphisms in CYP2E1, ALDH2, GSTM1 and GSTT1 in relation to the occurrence of mutant oncogene and tumor suppressor gene biomarkers that are attributable to VC exposure. The presence of the biomarkers for mutant ras-p21 and mutant p53 was found to be highly significantly associated with cumulative VC exposure (P for trend <0.0001). The presence of the CYP2E1 variant c2 allele was found to be significantly associated with the presence of either or both mutant biomarkers even after controlling for potential confounders including cumulative VC exposure (OR = 2.3, 95% CI = 1.2-4.1), and the effects of the c2 allele and VC exposure were approximately additive. GSTT1 null status was found to have an increased, but not significant association with the presence of either or both biomarkers after controlling for confounders (OR = 1.3, 95% CI = 0.8-2.0). These results suggest the existence of a possible gene-environment interaction between polymorphisms in the VC metabolic pathway and VC exposure that could contribute to the variable susceptibility to the mutagenic effects of VC in exposed populations.
Schindler
Jennifer
J
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 60 Haven Avenue, B-1, New York, NY, 10032, USA.
Li
Yongliang
Y
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 60 Haven Avenue, B-1, New York, NY, 10032, USA.
Marion
Marie-Jeanne
MJ
Unite de Recherche Virus des Hepatites et Pathologies Associee, INSERM, 151 cours Albert Thomas, 69494, Lyon Cedex 03, France.
Paroly
Arianne
A
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 60 Haven Avenue, B-1, New York, NY, 10032, USA.
Brandt-Rauf
Paul W
PW
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 60 Haven Avenue, B-1, New York, NY, 10032, USA. pwb1@columbia.edu.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000444:Aldehyde Dehydrogenase / Q000097:blood / Q000235:genetics; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D002273:Carcinogens / Q000378:metabolism*; D002617:Chemical Industry; D015331:Cohort Studies; D019392:Cytochrome P-450 CYP2E1 / Q000097:blood / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000097:blood / Q000235:genetics; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D016296:Mutagenesis; D009154:Mutation; D016273:Occupational Exposure; D011110:Polymorphism, Genetic; D016283:Proto-Oncogene Proteins p21(ras) / Q000097:blood / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000097:blood / Q000235:genetics; D014752:Vinyl Chloride / Q000378:metabolism*
D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D002273:Carcinogens; D019392:Cytochrome P-450 CYP2E1; D005982:Glutathione Transferase; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53; D014752:Vinyl Chloride; C096127:ALDH2 protein, human; C413545:glutathione S-transferase T1; C501009:HRAS protein, human