Epoxides are frequently formed as metabolites of unsaturated hydrocarbons by cytochrome P-450-dependent monooxygenase activity. Many arene and alkene oxides are known to react covalently with macromolecules and to transform cells in vitro, and some of these are ultimate carcinogens, mutagens and/or cytotoxins. We are studying various aspects of the enzymatic formation and metabolism of epoxides and of glycols and phenols which are products of subsequent epoxide biotransformation, in relationship to cell-selective and organ-selective toxicity of compounds metabolized to epoxides by both hepatic and extrahepatic tissues. Particular attention is given to the respiratory tract because this is a common site for pollutant-mediated damage. We are currently investigating the rabbit pulmonary glutathione S-transferases using a combination of biochemical (purification), immunochemical (polyclonal and monoclonal antibodies) and chemical (stereoselectivity with polycyclic arene oxides and alkene oxides as substrates) techniques; the biosynthesis and status of the tripeptide glutathione, which is important in detoxication of electrophilic metabolites, in Clara cells, alveolar type II cells, and alveolar macrophages isolated from rabbit lung; and the biochemical and immunochemical properties of pulmonary and renal UDP-glucuronosyltransferases.
