Abstract
Phenytoin, 5,5-diphenylhydantoin, is a widely used anticonvulsant agent with a variety of toxicities, including drug interactions. The formation of four oxidative metabolites, 4′-hydroxylated (4′-HPPH), 3′-hydroxylated (3′-HPPH), a catechol (3′,4′-diHPPH), and the 3′,4′-dihydrodiol form of phenytoin was examined in rat liver microsomes. In 11 cDNA-expressed rat P450 enzymes tested, CYP2C6 had the highest activities in 4′- and 3′-HPPH formation from phenytoin, followed only by CYP2C11. In contrast, CYP2C11 had high activity for 3′,4′-diHPPH formation from 4′-HPPH, followed by CYP2C6. The rates of 4′-HPPH and 3′,4′-diHPPH formation from phenytoin in liver microsomes in the presence of NADPH were significantly decreased by oral administration of phenytoin (300 mg/kg for 20 days) to rats, despite the increase in P450 contents. However, the cumene hydroperoxide-supported formation of 3′,4′-dihydrodiol and 4′-HPPH from phenytoin was induced by phenytoin administration. Hydrogen peroxide formation in reaction mixtures with NADPH was induced by the administration of phenytoin; however, the coupling ratio of phenytoin oxidation was decreased in phenytoin-induced liver microsomal P450 systems. These results suggested that phenytoin could not stimulate its own apparent oxidative metabolism by liver P450s induced with phenytoin administration. The increase of unmetabolized phenytoin and byproducts of oxygen generated in the phenytoin-induced liver microsomal P450 system may be involved in phenytoin-related drug toxicity.
Footnotes
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Send reprint requests to: Hiroshi Yamazaki, Ph.D., Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan. E-mail: yamazak{at}kenroku.kanazawa-u.ac.jp
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Supported in part by grants from the Ministry of Education, Science, Sports, and Culture of Japan, and the Ministry of Health and Welfare of Japan.
- Abbreviations used are::
- P450
- general term for cytochrome P450
- 4′-HPPH
- 5-(4′-hydroxyphenyl)-5-phenylhydantoin
- 3′-HPPH
- 5-(3′-hydroxyphenyl)-5-phenylhydantoin
- 3′,4′-diHPPH
- 5-(3′,4′-dihydroxyphenyl)-5-phenylhydantoin
- 3′,4′-dihydrodiol
- 5-(3′,4′-dihydroxy-1′,5′-cyclohexadien-1-yl)-5-phenylhydantoin
- NPR
- NADPHcytochrome P450 reductase
- b5
- cytochrome b5
- CYP1A2/NPR membranes
- membranes prepared from bacteria co-expressing CYP1A2 and NPR
- CuOOH
- cumene hydroperoxide
- LC
- liquid chromatography
- MS
- mass spectrometry
- Received November 6, 2000.
- Accepted January 4, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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