The main purpose or the proposed research is to determine the formation of potentially mutagenic metabolites in the 1,3-butadiene (BD) metabolic pathway leading to MI, a major urinary metabolite in humans. To understand this pathway, tissues from female mice and rats exposed to 3-butene-1,2-diol (BD-diol) will be used. BD-diol is the hypothesized immediate precursor of two potentially mutagenic metabolites, hydroxymethylvinylketone (HMVK) and 3,4-epoxy-1,2-butanediol (EB-diol), and is also a precursor to MI. The first hypothesis to be tested is that HMVK, but not EB-diol, is formed in B-diol exposed animals in an exposure-dependent manner and therefore contributes to mutagenicity observed in animals exposed to BD-diol and BD. The second hypothesis is that a hemoglobin adduct of HMVK can serve as a biomarker of BD-diol and BD exposure. In testing these hypotheses we will accomplish several aims. The first specific aim is to develop methods to measure promutagenic adducts formed by HMVK, specifically 1,N2-propanodeoxyguanosine adducts, in BD-diol exposed animals. Another specific aim is to develop methods to measure the hemoglobin adduct of HMVK in the exposed animals. The third specific aim is to measure DNA and hemoglobin adducts of EB-diol. The results of these experiments will demonstrate the formation and possible contribution to mutagenicity, of HMVK and EB-diol following metabolism of BD-diol. The final specific aim is to measure the HMVK adducts in BD exposed animals and humans. The proposed research will help explain a critical, but not fully understood, BD metabolic pathway. This will improve our understanding of BD metabolism as a whole and ultimately increase our ability to accurately assess the risk of BD to humans.
| Powley, Mark W; Walker, Vernon E; Li, Yutai et al. (2007) The importance of 3,4-epoxy-1,2-butanediol and hydroxymethylvinyl ketone in 3-butene-1,2-diol associated mutagenicity. Chem Biol Interact 166:182-90 |
| Powley, M W; Li, Y; Upton, P B et al. (2005) Quantification of DNA and hemoglobin adducts of 3,4-epoxy-1,2-butanediol in rodents exposed to 3-butene-1,2-diol. Carcinogenesis 26:1573-80 |
| Powley, Mark W; Jayaraj, Karupiah; Gold, Avram et al. (2003) 1,N2-propanodeoxyguanosine adducts of the 1,3-butadiene metabolite, hydroxymethylvinyl ketone. Chem Res Toxicol 16:1448-54 |
