Multiplicity of cytochrome P-450 species involved in theophylline metabolism in mouse hepatic microsomes.
To ascertain the multiplicity of the cytochrome P-450 (P-450) species participating in the individual metabolic conversion of theophylline by 8-hydroxylation, 3-demethylation and 1-demethylation in mice, kinetics were studied under various conditions using untreated and inducer-treated mouse hepatic microsomes. Eadie-Hofstee plots of 1-demethylation in untreated microsomes exhibited a straight line, whereas those of 8-hydroxylation and 3-demethylation were curved lines. The biphasic kinetics indicated the contribution of two P-450 populations to the respective metabolic pathways; one characterized by high affinity and low capacity, the other by low affinity and high capacity. The high affinity population was efficiently induced by beta-naphthoflavone (beta-NF), and was highly susceptible to inhibition by a specific CYP1A inhibitor. The low affinity population was sensitive to induction by phenobarbital (PB), and was markedly inhibited by preferential inhibitors for PB-inducible P-450 species. The present results indicated that two P-450 populations contributed to the theophylline metabolism in mouse hepatic microsomes, and that the high and low affinity populations corresponded, respectively, to CYP1A, and a PB-inducible P-450 species having a much higher capacity than CYP1A.
Konishi
H
H
Department of Hospital Pharmacy, Shiga University of Medical Science, Ohtsu, Japan.
Morita
K
K
Yamaji
A
A
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D003640:Dealkylation; D006900:Hydroxylation; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010634:Phenobarbital / Q000494:pharmacology; D013806:Theophylline / Q000378:metabolism* / Q000493:pharmacokinetics; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D007527:Isoenzymes; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; D010634:Phenobarbital