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, suggesting they are ultimate carcinogens, mutagens 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 stereochemical aspects of styrene oxidation, stereochemical and kinetic aspects of the biotransformation of model alkene (styrene 7,8-oxide) and polycyclic arene (benzo(a)pyrene 4,5-oxide) oxide substrates by cytosolic and purified glutathione transferases of diverse origin, the distribution and characteristics of components of the cytochrome P-450-containing monooxygenase system in vascular endothelium, the status of the tripeptide glutathione, which is important in detoxication of elctrophilic metabolites, in perfused lung, Clara cells, alveolar type II cells, and alveolar macrophages isolated from rabbit lung before and after exposure to electrophilic metabolites or conditions of oxidant stress (e.g., exposure to paraquat), and the biochemical and immunochemical properties of pulmonary and renal UDP-glucuronosyltransferases.
