In vivo effects of erythromycin, oleandomycin and erythralosamine derivatives on hepatic cytochrome P-450

• Published in: Biochemical pharmacology Vol. 40; no. 2; p. 223
• Main Authors: Delaforge, M, Sartori, E
• Format: Journal Article
• Language: English
• Published: England 15.07.1990
• Subjects: Animals; Cytochrome P-450 Enzyme System - metabolism; Dose-Response Relationship, Drug; Enzyme Induction - drug effects; Erythromycin - analogs & derivatives; Erythromycin - pharmacology; Iron - metabolism; Liver - drug effects; Liver - enzymology; Male; Oleandomycin - pharmacology; Rats; Rats, Inbred Strains; Structure-Activity Relationship
• ISSN: 0006-2952
• DOI: 10.1016/0006-2952(90)90682-B

Rats have been treated with several derivatives of the erythromycin, erythralosamine or oleandomycin series, in order to compare their ability to induce cytochrome P-450 and to form stable 456 nm-absorbing cytochrome P-450 metabolite complexes. The data obtained confirm that the cytochromes P-450 induced in rats by various macrolides are similar to that induced by pregnenolone 16 alpha-carbonitrile: the cytochrome P-450 IIIA1 isozyme. It showed that: (i) formation of a stable inhibitory 456 nm-absorbing cytochrome P-450 complex is not a prerequisite for cytochrome P-450 induction but enhances induction by stabilization of the IIIA isozyme. Therefore, the best inducers lead also to the maximal in vivo amounts of cytochrome P-450 metabolite complex (except for 2'MBEM); (ii) affinity for cytochrome P-450 IIIA1 is not directly involved for induction; and (iii) hydrophobicity favors induction and formation of complexes. Structural factors are also involved.