Toxicology Letters, 30 (1986) 273-278 Elsevier 273 TOXLett. 1554 STEREOCHEMICAL CONSIDERATIONS ON THE INHIBITION OF HEPATIC EPOXIDE HYDROLASE BY SOME PESTICIDES AND THEIR EPOXIDES (Pesticides; epoxides; metabolism; epoxide hydrolase) D. COVAa, A. ARNOLDIb, R. COLOMBO’ and L. ROSSINI” ‘Department of Pharmacology, CNR Center of Cytopharmacology, University of Milan, Via Vanvitelli 32, 20129 Milan, bInstitute of General Biochemistry, University of Milan, Via Celoria 2, 20133 Milan, and ‘Department of Biomedical Sciences and Technology, University of Milan, St. Raphael Hospital, Via Olgettina 60, Milan (Italy) (Received October 25th, 1985) (Accepted January 29th, 1986) SUMMARY The present studies identify the steric factors involved in the hydration of epoxide intermediates of some pesticides by hepatic epoxide hydrolase. Investigations were carried out regarding the formation of reactive epoxide intermediates and their different interactions with the hepatic epoxide hydrolase. Some pesticides and their parent epoxides were selected on the basis of the steric hindrance on the oxirane ring. The results indicate that the inhibition of this enzyme depends on the steric hindrance produced by substituents on the oxirane ring of these pesticides. Mono- and di-substituted oxiranes are good substrates of the epoxide hydrolase and non-competitive inhibitors of the hydration of styrene oxide, while tri-substituted epoxides are virtually inactive on inhibiting the hepatic epoxide hydrolase activity. INTRODUCTION The importance of epoxidation in the metabolism of pesticides has become ap- parent only in recent years with the evidence that unstable epoxides are in- termediates in oxidative hydroxylation. Generally these reactions are catalyzed by epoxide hydrolase, a microsomal enzyme converting epoxides into diols, which are less toxic than most of their parent compounds [l-3]. We examined some pesticides and their epoxide intermediates reported in Fig. 1; specifically we tested at first vinclozolin epoxide, a mono-substituted oxirane formed during the bio-transformation of vinclozolin, an antifungal compound 0378-4274/86/s 03.50 0 Elsevier Science Publishers B.V. (Biomedical Division)