In vitro interaction of rat liver cytochromes P-450 with erythromycin, oleandomycin and erythralosamine derivatives. Importance of structural factors.
Several derivatives of the erythromycin, erythralosamine and oleandomycin series have been prepared. Their abilities to bind to rat liver microsomal cytochrome P-450 and to lead to the formation of stable 456 nm absorbing cytochrome P-450-metabolite complexes after their oxidative microsomal metabolism in vitro have been compared. The obtained data confirmed that cytochrome P-450 induced in rats either by macrolides or by 16 alpha-pregnenolone carbonitrile were the major isozymes involved in the binding of macrolides to liver microsomes and in metabolite-complex formation. They showed that (i) hydrophobicity was in general a beneficial factor for these two properties, (ii) the presence of a bulky substituent in position 3 of erythromycin dramatically decreased their affinity for these isozymes, and (iii) the simultaneous presence of bulky substituents in position 2' and 3 prevented iron-metabolite complex formation. These results led to the selection of two compounds, erythralosamine-2'-benzoate and erythralosamine-2',3-diacetate, which exhibited a particularly high affinity for macrolide inducible cytochrome P-450 and were very good precursors of cytochrome P-450-iron-metabolite complex formation.
Sartori
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E
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UA 400 CNRS, Paris, France.
Delaforge
M
M
Mansuy
D
D
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003573:Cytochrome b Group / Q000378:metabolism; D015786:Cytochromes b5; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009827:Oleandomycin / Q000031:analogs & derivatives / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D013329:Structure-Activity Relationship; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D003573:Cytochrome b Group; C045512:erythralosamine; C060074:erythralosamine-2',3-diacetate; D019324:beta-Naphthoflavone; D004917:Erythromycin; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D009827:Oleandomycin; D010634:Phenobarbital