RT Journal Article
SR Electronic
T1 Self-induction by erythromycin of its own transformation into a metabolite forming an inactive complex with reduced cytochrome P-450.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 509
OP 514
VO 218
IS 2
A1 G Danan
A1 V Descatoire
A1 D Pessayre
YR 1981
UL http://jpet.aspetjournals.org/content/218/2/509.abstract
AB Erythromycin, 0.3 mM, elicited a small reverse type I binding spectrum with, and was slowly demethylated by, cytochrome P-450 from control rats. No absorption peak at 456 nm could be detected upon incubation of 0.3 mM erythromycin with NADPH and control microsomes. No complex formed in vivo could be detected in microsomes isolated 2 hr after a single dose of erythromycin, 2 mmol.kg-1 p.o. Repeated administration of erythromycin, 2 mmol.kg-1 p.o. daily for 4 days increased hepatic microsomal protein concentration, NADPH-cytochrome c reductase activity, the amplitude of the reverse type I binding spectrum of erythromycin and erythromycin demethylase activity. Microsomes isolated from rats treated with repeated doses of erythromycin exhibited a marked absorption peak at 456 nm. The absorption at 456 nm was further increased upon incubation with erythromycin and NADPH. It disappeared upon addition of 50 muM potassium ferricyanide. Disruption of the complex with potassium ferricyanide markedly increased the CO-binding capacity of dithionite-reduced microsomes. It further increased the amplitude of the reverse type I binding spectrum of erythromycin and erythromycin demethylase activity and increased ethylmorphine N-demethylase and benzo[a]pyrene hydroxylase activities. It is concluded that erythromycin induces its own transformation into a metabolite which forms a inactive 456-nm absorbing complex with the iron (II) of cytochrome P-450.