RT Journal Article
SR Electronic
T1 Inactivation of cytochrome P-450 by a troleandomycin metabolite. Protective role of glutathione.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 685
OP 691
VO 224
IS 3
A1 D Pessayre
A1 M Tinel
A1 D Larrey
A1 B Cobert
A1 C Funck-Brentano
A1 G Babany
YR 1983
UL http://jpet.aspetjournals.org/content/224/3/685.abstract
AB Troleandomycin, a macrolide antibiotic, has been shown to be demethylated and oxidized into a metabolite which forms an inactive complex with the iron(II) of cytochrome P-450. The role of glutathione in the metabolism of troleandomycin was investigated. Administration of troleandomycin (1 mmol X kg-1 p.o.) decreased the concentration of glutathione in the liver. The depletion of glutathione was increased in rats pretreated with phenobarbital and decreased in rats pretreated with CoCl2. In vitro, an inverse relationship was found between the concentration of glutathione in the incubation mixture and the appearance of the cytochrome P-450-troleandomycin metabolite complex. Glutathione, however, did not inhibit the demethylation of troleandomycin and did not destroy the cytochrome P-450-troleandomycin metabolite complex. The in vitro protective effect of glutathione was reproduced by cysteine but not by glycine. In vivo, decreasing the concentration of glutathione in the liver by food deprivation or by the administration of diethylmaleate increased the formation of the cytochrome P-450-troleandomycin metabolite complex. These results indicate that glutathione is depleted by a troleandomycin metabolite in vivo, whereas glutathione protects against the formation of the inactive cytochrome P-450-troleandomycin metabolite complex in vitro and in vivo.