Involvement of CYP2E in 8-Hydroxylation of Theophylline in Mouse Hepatic Microsomes-Difference from Its N-Demethylations
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概要
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We examined which cytochrome P-450 (P-450) species other than CYP1A participates in the oxidative metabolism of theophylline (TP) in mouse hepatic microsomes. Among the three metabolic pathways of TP, only 8-hydroxylation was selectively enhanced by acetone, a potent inducer of CYP2E. We assumed that two P-450 populations with different metabolic ability were involved in this metabolic process, and kinetic analyses revealed that the enhancement was due to the induction of a high-capacity P-450 population. The 8-hydroxylation at a substrate concentration, where most of the total activity was attributed to the catalysis of the high-capacity phase, was markedly impaired by CYP2E inhibitors such as 4-methylpyrazole and aminoacetonitrile, whereas the N-demethylations were little affected by these agents. The activity of TP 8-hydroxylation was significantly correlated with that of p-nitrophenol hydroxylation, a probe for CYP2E, in untreated microsomes. The activities of these oxidative reactions were modified to a similar degree by known enzyme inhibitors with a range of inhibitory potencies and affinity for P-450 isoforms. On the other hand, a relationship between TP N-demethylations and p-nitrophenol hydroxylation was not apparent, but there was a nehavioral similarity between the two types of N-demethylations. The results indicated that TP 8-hydroxylation, which accounts for a large portion of TP oxidations, involves CYP2E, and that its N-demethylations are mediated by a common or closely similar P-450 species distinct from CYP2E.
- 公益社団法人日本薬学会の論文
- 1996-04-15
著者
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MORITA Kunihiko
Department of Hospital Pharmacy, Keio University School of Medicine
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KONISHI Hiroki
Department of Hospital Pharmacy, of Shiga University of Medical Science
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YAMAJI Akira
Department of Hospital Pharmacy, of Shiga University of Medical Science
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Yamaji Akira
Department Of Hospital Pharmacy Shiga University Of Medical Science
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Konishi Hiroki
Department Of Hospital Pharmacy Of Shiga University Of Medical Science
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Morita Kunihiko
Department Of Hospital Pharmacy Keio University School Of Medicine
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Morita Kunihiko
Department Of Hospital Pharmacy Shiga University Of Medical Science
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Morita Kunihiko
Department Of Clinical Laboratory Nisshin Orido Hospital
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