‘IN VITRO’ INTERACTIONS OF MONENSIN WITH HEPATIC XENOBIOTIC METABOLIZING ENZYMES

Abstract

Monensin, a polyether ionophore antibiotic used worldwide for its anticoccidial and growth-promoting properties, is reported to act as anin vivoinducer or inhibitor of drug-metabolizing enzyme systems in various species according to dosage regimens and duration of exposure. When incubated at a concentration up to 0.25 mmwith hepatic subfractions from either untreated- (UT) or phenobarbital- (PB) induced rats, monensin did not induce appreciable changes in cytochrome P450 content and functions as well as in NADPH cytochromecreductase or glutathioneS-transferase. On the other hand, monensin concentrations ranging from 0.05 to 0.25 mmproved to increase the initial rate of NADPH oxidation up to 63% in UT-microsomes, and thein vitroaddition of the ionophore to microsomes resulted in the formation of a characteristic type I binding spectrum. The rate of monensin O-demethylation was 0.34±0.01 and 0.99±0.07 nmol min−1per mg of protein in UT- and PB-microsomes, respectively. In the latter, this reaction was consistently depressed when NADPH was omitted or replaced with NADH, or upon the addition of 1 mmmetyrapone, a known P450 inhibitor. It is concluded that monensin does not behave as a directin vitroinhibitor of drug metabolizing enzymes and appears to be a substrate of P450-dependent monooxygenases.