Mercapturic Acid Urinary Metabolites of 3-Butene-1,2-diol as in Vivo Evidence for the Formation of Hydroxymethylvinyl Ketone in Mice and Rats

Abstract

3-Butene-1,2-diol (BDD), a major metabolite of 1,3-butadiene (BD), can readily be oxidized to hydroxymethylvinyl ketone (HMVK), a Michael acceptor. In previous studies, 4-(N-acetyl-l-cystein-S-yl)-1,2-dihydroxybutane (DHB), a urinary metabolite of BD that was used to assess human BD exposure, was suggested to be a metabolite of HMVK, but DHB formation from BDD and the formation of the DHB precursor 4-(N-acetyl-l-cystein-S-yl)-1-hydroxy-2-butanone (HB) have not been previously investigated. In the current study, four HMVK-derived mercapturic acids [DHB, HB, 3-(N-acetyl-l-cystein-S-yl)propan-1-ol (POH), and 3-(N-acetyl-l-cystein-S-yl)propanoic acid (PA)] were identified in the urine of mice and rats given BDD (284-2272 micromol/kg, i.p.) based on GC/MS analyses and comparisons with synthetic standards after esterification and silylation of the carboxyl and hydroxyl groups, respectively. The combined amounts of the mercapturic acids excreted after BDD exposure were dose-dependent and were mostly similar between mice and rats given equivalent doses of BDD. The mercapturic acids accounted for a greater fraction of the administered BDD dose as the dose was lowered, suggesting that HMVK formation represents a prominent route for BDD metabolism in both mice and rats. The major mercapturic acid excreted by mice was DHB, whereas rats excreted equivalent amounts of DHB and HB. The levels of POH or PA were significantly lower in both species relative to DHB or HB. The observed species differences in the excretion of DHB and HB were thought to be due to differences in the capacity of mice and rats to reduce HB to DHB.

1,3-Butadiene Exposure and Metabolism among Japanese American, Native Hawaiian, and White Smokers

“…In a small in vitro study, the investigators found that EB can be detoxified by epoxide hydrolase (EH)(36), which is the major detoxification pathway for this epoxide in rats, and likely plays a significant role in humans. EH mediated hydrolysis of EB and further biotransformation of the resulting diol by alcohol dehydrogenase (ADH) result in the formation of hydroxyl methyl vinyl ketone (HMVK)(37). Alternatively, EB and HMVK can be conjugated with glutathione and excreted in urine as the corresponding mercapturic acids, MHBMA and DHBMA(38).…”

Genetic Determinants of 1,3-Butadiene Metabolism and Detoxification in Three Populations of Smokers with Different Risks of Lung Cancer

“…BD is metabolically activated to several DNA reactive species, including 3,4-epoxybut-1-ene (EB), 1,2,3,4-diepoxybutane (DEB), hydroxymethylvinyl ketone (HMVK), and 3,4-epoxy-1,2-butanediol (EBD) (Scheme 1) (27–29). Epoxidation of BD to EB is catalyzed by cytochrome P450 monooxygenases 2E1 and 2A6 (CYP2E1 and 2A6) (30).…”

“…Epoxidation of BD to EB is catalyzed by cytochrome P450 monooxygenases 2E1 and 2A6 (CYP2E1 and 2A6) (30). Epoxide hydrolase (EH)-mediated hydrolysis of EB gives rise to 1-butene-3,4-diol (EB-diol), which is subsequently converted to HMVK by alcohol dehydrogenase (ADH) (29,31). Alternatively, EB can be further epoxidized by CYP2E1 to 1,2,3,4-diepoxybutane (DEB) (28), which in turn can be hydrolyzed to epoxy-1,2-butanediol (EBD) (32,33).…”

High throughput HPLC–ESI−-MS/MS methodology for mercapturic acid metabolites of 1,3-butadiene: Biomarkers of exposure and bioactivation

“…8;10 EB can undergo further oxidation to 1,2,3,4-diepoxybutane (DEB) or epoxide hydrolysis to 3-butene-1,2-diol (EB-diol), which can be further metabolized to hydroxymethyl vinylketone (HMVK). 11–13 Alternatively, EB-diol can be oxidized by CYP2E1 to form 3,4-epoxy-1,2-butanediol (EBD). 8;14 If not detoxified by epoxide hydrolase (EH) or glutathione S-transferase (GST), EB, EBD, HMVK, and DEB can alkylate DNA to form promutagenic nucleobase adducts, which are thought to be responsible for the adverse biological effects of BD.…”