1,3-Butadiene (BD, CH2CHCHCH2) is used in the production of plastics and rubber and hence occupational exposure to the compound by humans is unavoidable. BD is a potent carcinogen in mice and a weak carcinogen in rats. BD is metabolized to the epoxide metabolite, epoxybutene (EB), which is further metabolized to diepoxybutane (DEB). Cancer potency in rats and mice has been correlated with measured DEB concentrations in blood and tissues. Metabolic activation is probably required for BD toxicity to occur, with Cytochrome P450 2E1 (CYP2E1) suspected to be the enzyme responsible for BD activation to the epoxide metabolites, EB and DEB. The goal of this research is to test the hypothesis that CYP2E1 is the primary isozyme responsible for the metabolism and toxicity of BD; if this hypothesis is true, mice which lack a functional gene for CYP2E1 (cyp2e1-/-) should demonstrate reduced BD metabolism and toxicity under various exposure scenarios. This hypothesis will be tested under four specific aims: (1) determine BD dosimetry, genotoxicity and cytotoxicity in cyp2e1-/- mice, relative to cyp2e1+/+ mice, (2) quantitate the rate of metabolism of BD in cyp2e1-/- mice, relative to cyp2e1+/+ mice, (3) determine the role of CYP2E1 int he metabolism and resulting toxicity of EB, and (4) measure N7-guanine and N3-adenine adduct levels in DNA of cyp2e1-/- mice, relative to cyp2e1+/+ mice. If CYP2E1 is involved in BD metabolism and resultant toxicity, then the cyp2e1-/- mice should demonstrate reduced levels of genotoxicity and cytotoxicity, lower tissue concentrations of EB and DEB and decreased DNA adduct levels. If BD metabolism by CYP2E1 is related to toxicity, then the level of CYP2E1 in humans should be an important indicator of risk, since humans demonstrate variable levels of CYP2E1.
| Jackson, T E; Lilly, P D; Recio, L et al. (2000) Inhibition of cytochrome P450 2E1 decreases, but does not eliminate, genotoxicity mediated by 1,3-butadiene. Toxicol Sci 55:266-73 |
