STEREOCHEMICAL ASPECTS OF 1,3-BUTADIENE METABOLISM AND TOXICITY IN RAT AND MOUSE-LIVER MICROSOMES AND FRESHLY ISOLATED RAT HEPATOCYTES

1,3-Butadiene (ED) is a gas used heavily in the rubber and plastics in dustry. ED and its epoxide metabolites have been shown to be carcinoge nic and mutagenic in rodents, and ED has been classified by IARC as a group 2A carcinogen. We have examined the role of stereochemistry in s pecies-dependent metabolism and toxicity of ED. Diastereo- and enantio selective synthetic routes to butadiene monoxide (BMO), butadiene biso xide (BBO), and 3,4-epoxybutane-1,2-diol isomers have been developed. These routes have allowed the development of chiral gas chromatographi c and GC/MS analytical procedures for quantitation of these metabolite s in biological experiments. We have utilized hepatic microsomes from male B6C3F1 mice and hepatic microsomes and intact hepatocytes from ma le Sprague-Dawley rats as experimental systems. At 30 min, BMO product ion from ED was two times higher in mouse hepatic microsomes than in r ats, and stereoselective analysis was used to determine the relative f ormation of (R)- and (S)-BMO. Formation of BBO from both (R)- and (S)- BMO was characterized in rat and mouse microsomal systems. As expected , more BBO was formed in mouse hepatic microsomes (3-4-fold) than in r at hepatic microsomes. No difference in total BBO formed from either i somer was observed in rat microsomes, but in mouse microsomes signific antly more BBO was produced from (S)-BMO than from(R)-BMO. The cytotox icity of each BMO and BBO enantiomer was examined in freshly isolated rat hepatocytes. (R)-BMO showed greater cytotoxicity than (S)-BMO. Ste reospecific cytotoxicity was also observed using BBO enantiomers and ( meso)-BBO was more cytotoxic than either the (R:R) or the (S:S)-BBO. T he results show that stereochemistry plays an important role in ED met abolism and cytotoxicity and for the purposes of risk assessment needs to be compared across species.