Species and strain differences in xenobiotic-mediated induction of hepatic drug metabolizing enzymes

The nature of extent of drug metabolizing enzyme induction by exogenous compounds is often dependent on the animal being investigated, the chemical nature of the xenobiotic and the specific dosing protocol. Herein, the effects of both traditional and nontraditional inducing agents on the biotransformation of isozyme-selective substrates by hepatic drug metabolizing enzymes were investigated in the rat, hamster and three mouse strains. The N-substituted imidazoles clotrimazole, N-benzylimidazole and nafimidone were more potent in inducing Phase I monooxygenase (cytochrome P450) and Phase II conjugative (microsomal UDP-glucuronosyltransferase and cytosolic glutathione S-transferase) activities in the rat than in the hamster and mouse. These species differences were especially noteworthy for the O-deethylation of ethoxyresorufin, a monooxygenase activity purported to be induced by xenobiotic binding of a cytosolic receptor. In mice or hamsters, N-benzylimidazole and nafimidone caused only small increases in ethoxyresorufin O-deethylase activity, compared to the major inductions seen in rats. Marked species and strain variation was also observed in the induction caused by traditional inducing agents, including dexamethasone. In one strain of mouse, dexamethasone displayed a Phase I 'phenobarbital-like' inductive property and, in another strain, caused a Phase II '$/beta$-naphthoflavone-like' induction. Dexamethasone also induced hamster monooxygenase activity in a manner similar to that reported for ethanol-mediated induction in rats. Prolonged enteral exposure to the glutathione-depleting agent buthionine sulfoximine selectively induced Phase II UDP-glucuronosyltransferase and glutathione S-transferase activities in rats. The Phase II selective effect caused by buthionine sulfoximine was not evident in mice. In buthionine sulfoximine-treated rats, the increase in in vitro UDP-glucuronosyltransferase activity was paralleled by enhanced partial clearance and urinary recovery of acetaminophen-glucuronide following intravenous acetaminophen administration. These findings suggest that the ostensible isozyme-specific xenobiotic substrate assays that have been used and characterized, historically, in rats, to model induction may be inappropriate in other species. Furthermore, the induction of Phase II enzymes by buthionine sulfoximine has not been previously reported and is a significant effect to be considered in studies using prolonged buthionine sulfoximine treatments. The possible relationship between glutathione availability and the induction of conjugative enzymes is discussed.