Abstract
The role of cytochrome P-450s (CYPs) inS-mephobarbital N-demethylation was investigated by using human liver microsomes and cDNA-expressed CYPs. Among the 10 cDNA-expressed CYPs studied (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), only CYP2B6 could catalyze S-mephobarbitalN-demethylation. The apparentKm values of human liver microsomes forS-mephobarbital N-demethylation were close to that of cDNA-expressed CYP2B6 (about 250 μM). TheN-demethylase activity of S-mephobarbital in 10 human liver microsomes was strongly correlated with immunodetectable CYP2B6 levels (r = 0.920,p < .001). Orphenadrine (300 μM), a CYP2B6 inhibitor, inhibited the N-demethylase activity ofS-mephobarbital in human liver microsomes to 29% of control activity. Therefore, it appears that CYP2B6 mainly catalyzesS-mephobarbital N-demethylation in human liver microsomes.
Footnotes
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Send reprint requests to: Kaoru Kobayashi, Ph.D., Laboratory of Biochemical Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, Chiba University, Yayoi-cho 1–33, Inage-ku, Chiba 263-8522, Japan. E-mail: kaoruk{at}p.chiba-u.ac.jp
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↵1 Present address: Laboratory of Biochemical Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan.
- Abbreviation used is::
- CYP
- cytochrome P-450
- Received July 13, 1999.
- Accepted September 3, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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