Mechanism-based Inhibition of CYP1A1 and CYP3A4 by the Furanocoumarin Chalepensin
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- UENG Yune-Fang
- Laboratory of Drug Metabolism, National Research Institute of Chinese Medicine Institute of Medical Science, Taipei Medical University Department of Pharmacology, School of Medicine, National Yang-Ming University
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- CHEN Chien-Chih
- Laboratory of Drug Metabolism, National Research Institute of Chinese Medicine Department of Biotechnology, Hungkuang University
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- YAMAZAKI Hiroshi
- Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University
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- KIYOTANI Kazuma
- Laboratories for Pharmacogenetics, Genotyping Development, and Medical Informatics, RIKEN Center for Genomic Medicine
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- CHANG Yu-Ping
- Laboratory of Drug Metabolism, National Research Institute of Chinese Medicine
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- LO Wei-Shang
- Laboratory of Drug Metabolism, National Research Institute of Chinese Medicine
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- LI Ding-Tzai
- Mass Solution Technology Co., Ltd.
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- TSAI Pei-Lun
- Mass Solution Technology Co., Ltd.
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抄録
The cytochrome P450 (P450, CYP) 2A6 inhibitor chalepensin was found to inhibit human CYP1A1, CYP1A2, CYP2A13, CYP2C9, CYP2D6, CYP2E1, and CYP3A4 to different extents. CYP1A1 and CYP3A4 underwent pronounced mechanism-based inactivation by chalepensin and had the smallest IC50 ratios of inhibition with NADPH-fortified pre-incubation (IC50(+)) to that without pre-incubation (IC50(−)). CYP2E1 had the least susceptibility to mechanism-based inactivation. This inactivation of CYP1A1 and CYP3A4 exhibited time-dependence, led to a loss of spectrophotometrically detected P450, and could not be fully recovered by dialysis. Pre-incubation with chalepensin did not affect NADPH-P450 reductase activity. Cytosol-supported glutathione conjugation protected CYP3A4 but not CYP1A1 against the inactivation by chalepensin. Cytosolic decomposition of chalepensin may contribute partially to the protection. The high epoxidation activities of CYP1A1, CYP2A6, and CYP3A4 were in agreement with their pronounced susceptibilities to mechanism-based inactivation by chalepensin. Considering both the IC50 values and inactivation kinetic parameters, the threshold concentrations of chalepensin for potential drug interactions through inhibition of CYP2A6 and CYP3A4 were estimated to be consistently low. These results demonstrate that chalepensin inhibits multiple P450s and that epoxidation activity is crucial for the potential drug interaction through mechanism-based inhibition.<br>
収録刊行物
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- Ｄｒｕｇ Ｍｅｔａｂｏｌｉｓｍ ａｎｄ Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ
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Ｄｒｕｇ Ｍｅｔａｂｏｌｉｓｍ ａｎｄ Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ 28 (3), 229-238, 2013
日本薬物動態学会
