The long-term objective of this research is to develop genetically-based biomarker assays for identifying individuals with increased health-risk from exposure to carcinogens. The specific objective is to identify genetic determinants of vinyl chloride-metabolism and DNA lesion repair for use as biomarkers to assess a priori susceptibility to vinyl chloride-induced liver cancer in humans. Angiosarcoma of the liver (ASL) will be used as a working model. ASL is a devastating disease with a 100% rate of mortality. There is a strong association between ASL and occupational exposure to vinyl chloride (VC). ASL occurs at a constant rate over a broad range of vinyl chloride (VC) exposure, suggesting the existence of a high risk phenotype in humans. The mutagenic potential of VC is controlled by three processes: 1) It is increased by cytochrome P4502E1 (CYP2E1)-mediated bioactivation, 2) it is decreased through glutathione S-transferase (GST)-mediated conjugation of metabolites to glutathione, and, 3) it is decreased through methylpurine-DNA glycosylase (MPG)-initiated removal of etheno-DNA adducts. The model is well defined because it includes: a unique source of subjects exposed to VC, liver tissue samples from subjects with ASL, a well characterized VC-associated tumor cell line, the causative agent (VC and its metabolite), and the likelihood of genetic susceptibility. The investigators hypothesize that susceptibility to VC-induced angiosarcoma of the liver is associated with genetic determinants of aberrant CYP2E1, GST and/or MPG phenotypes. To evaluate this hypothesis, they will: 1) screen individuals with ASL for specific mutations of the CYP2E1 and MPG genes which may lead to a high risk phenotype; 2) develop methods to screen a human population for the prevalence of CYP2E1 and MPG mutant alleles identified in ASL subjects, and, 3) determine the relationship between polymorphism in CYP2E1, GST, and/or MPG and susceptibility to liver cancer in a population of individuals exposed to vinyl chloride. This research is expected to provide a mechanism to rapidly and effectively identify individuals currently working in the vinyl monomer industry who may be at high risk for acquiring VC-induced ASL. It will also provide a working model for assessing the role of CYP2E1, GST, and MPG in exposure-linked health outcome. The results will provide a genetic-based model useful in approaching a variety of other diseases caused from environmental exposure to xenobiotics.
| Qiu, Ling O; Linder, Mark W; Antonino-Green, Deborah M et al. (2004) Suppression of cytochrome P450 2E1 promoter activity by interferon-gamma and loss of response due to the -71G>T nucleotide polymorphism of the CYP2E1*7B allele. J Pharmacol Exp Ther 308:284-8 |
