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The effect of genetic polymorphisms in the vinyl chloride metabolic pathway on mutagenic risk
Journal article   Open access   Peer reviewed

The effect of genetic polymorphisms in the vinyl chloride metabolic pathway on mutagenic risk

Jennifer Schindler, Yongliang Li, Marie-Jeanne Marion, Arianne Paroly and Paul W Brandt-Rauf
Journal of human genetics, v 52(5), pp 448-455
2007
DOI: https://doi.org/10.1007/s10038-007-0134-5
PMID: 17384900
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://www.nature.com/articles/jhg200758.pdfView
Published, Version of Record (VoR) Open
url
https://doi.org/10.1007/s10038-007-0134-5View
Published, Version of Record (VoR) Open

Abstract

Adult Aged Aged, 80 and over Aldehyde Dehydrogenase - blood Aldehyde Dehydrogenase - genetics Aldehyde Dehydrogenase, Mitochondrial Carcinogens - metabolism Chemical Industry Cohort Studies Cytochrome P-450 CYP2E1 - blood Cytochrome P-450 CYP2E1 - genetics Genetic Predisposition to Disease Genotype Glutathione Transferase - blood Glutathione Transferase - genetics Humans Male Metabolic Networks and Pathways Middle Aged Mutagenesis Mutation Occupational Exposure Polymorphism, Genetic Proto-Oncogene Proteins p21(ras) - blood Proto-Oncogene Proteins p21(ras) - genetics Tumor Suppressor Protein p53 - blood Tumor Suppressor Protein p53 - genetics Vinyl Chloride - metabolism
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.

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Web of Science research areas
Genetics & Heredity
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