CYTOCHROME-P450 INDUCTION AND METABOLISM OF ALKOXYRESORUFINS, ETHYLMORPHINE AND TESTOSTERONE IN CULTURED-HEPATOCYTES FROM GOATS, SHEEP AND CATTLE

Very little is known of cytochrome P450 (P450) pattems and enzyme char acteristics in food-producing animal species. Oxidative metabolism of alkoxyresorufins, ethylmorphine (EtM) and testosterone (TST) was used to monitor the effects of the P450 inducers phenobarbital (PB), beta-n aphthoflavone (BNF), dexamethasone (DEX) and triacetyloleandomycin (TA O) in primary cultured hepatocytes from goats, sheep and cattle. BNF e ffectively and specifically induced ethoxyresorufln deethylase (>20-fo ld), indicating the presence of an inducible P450 IA form, and down-re gulated EtM demethylation and most selected TST hydroxylations. In non -induced hepatocyte cultures, TST was metabolized to 6beta-, 2beta-, 1 2beta-, and 11alpha-hydroxy-TST (OHT). PB and, to a lesser extent, DEX non-specifically induced all OHT formations, and EtM demethylation. T AO almost completely inhibited OHT formation and EtM demethylation. Th ese results indicate the involvement of principally one P450 form, or a restricted number of related P450 forms, presumably belonging to the P450 3A subfamily. In western blot analysis, cross reactivity was fou nd with rat anti-P450 3A1 and anti-sheep P450 3A. A more specific PB e ffect was observed for 16alpha-OHT, which may be formed though a rumin ant P450 2B form. None of the inducers influenced pentoxyresorufin dep entylase (PROD) or EtM O-deethylation. Metabolite pattems and inducibi lity of selected activities in ruminant hepatocytes are in accordance with previous findings in goats in vivo. Cytochrome P450 characteristi cs in ruminants appear to differ from those in rats whereas similariti es to the situation in humans appear to exist.