'In vitro' interactions of monensin with hepatic xenobiotic metabolizing enzymes.
Monensin, a polyether ionophore antibiotic used worldwide for its anticoccidial and growth-promoting properties, is reported to act as anin vivo inducer 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 mM with 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 cytochrome c reductase or glutathione S-transferase. On the other hand, monensin concentrations ranging from 0.05 to 0.25 mM proved to increase the initial rate of NADPH oxidation up to 63% in UT-microsomes, and the in vitro addition 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-1 per 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 mM metyrapone, a known P450 inhibitor. It is concluded that monensin does not behave as a direct in vitro inhibitor of drug metabolizing enzymes and appears to be a substrate of P450-dependent monooxygenases.
Ceppa
L
L
Dipartimento di Patologia Animale, settore di Farmacologia e Tossicologia, Univerisità di Torino, Italia.
Dacasto
M
M
Carletti
M
M
Montesissa
C
C
Nebbia
C
C
D000818:Animals; D003049:Coccidiostats / Q000378:metabolism / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D008985:Monensin / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D003049:Coccidiostats; D003577:Cytochrome P-450 Enzyme System; D008985:Monensin