Major role of the CYP2Cisozymes in deamination of amphetamine and benzphetamine : evidence for the quinidine- specific inhibition of the reactions catalysed by rabbit enzyme

the late S. SHIIYAMA Faculty of Pharmaceutical Sciences, Kyushu University 62, 3- 1- 1 Maidashi , Higashiku, Fukuok a 812- 82, Japan Institut e of Commun ity Medicine, University of Tsukuba, Tsukuba , Ibaraki 305, Japan Department of Molecular and Medical Pharmacology, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90024, USA Department of Food and Nutrition, Nakamura Gakuen University, 5- 7- 1 Befu, Johnan-ku, Fukuoka 814- 01, Japan

T. SOEJIMA-OHKUMA Faculty of Pharmaceutical Sciences, Kyushu University 62, 3- 1- 1 Maidashi , Higashiku, Fukuok a 812- 82, Japan Institut e of Commun ity Medicine, University of Tsukuba, Tsukuba , Ibaraki 305, Japan Department of Molecular and Medical Pharmacology, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90024, USA Department of Food and Nutrition, Nakamura Gakuen University, 5- 7- 1 Befu, Johnan-ku, Fukuoka 814- 01, Japan

S. HONDA Faculty of Pharmaceutical Sciences, Kyushu University 62, 3- 1- 1 Maidashi , Higashiku, Fukuok a 812- 82, Japan Institut e of Commun ity Medicine, University of Tsukuba, Tsukuba , Ibaraki 305, Japan Department of Molecular and Medical Pharmacology, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90024, USA Department of Food and Nutrition, Nakamura Gakuen University, 5- 7- 1 Befu, Johnan-ku, Fukuoka 814- 01, Japan

Y. KUMAGAI Faculty of Pharmaceutical Sciences, Kyushu University 62, 3- 1- 1 Maidashi , Higashiku, Fukuok a 812- 82, Japan Institut e of Commun ity Medicine, University of Tsukuba, Tsukuba , Ibaraki 305, Japan Department of Molecular and Medical Pharmacology, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90024, USA Department of Food and Nutrition, Nakamura Gakuen University, 5- 7- 1 Befu, Johnan-ku, Fukuoka 814- 01, Japan

A. K. CHO Faculty of Pharmaceutical Sciences, Kyushu University 62, 3- 1- 1 Maidashi , Higashiku, Fukuok a 812- 82, Japan Institut e of Commun ity Medicine, University of Tsukuba, Tsukuba , Ibaraki 305, Japan Department of Molecular and Medical Pharmacology, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90024, USA Department of Food and Nutrition, Nakamura Gakuen University, 5- 7- 1 Befu, Johnan-ku, Fukuoka 814- 01, Japan

H. YAMADA Faculty of Pharmaceutical Sciences, Kyushu University 62, 3- 1- 1 Maidashi , Higashiku, Fukuok a 812- 82, Japan Institut e of Commun ity Medicine, University of Tsukuba, Tsukuba , Ibaraki 305, Japan Department of Molecular and Medical Pharmacology, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90024, USA Department of Food and Nutrition, Nakamura Gakuen University, 5- 7- 1 Befu, Johnan-ku, Fukuoka 814- 01, Japan

K. OGURI Faculty of Pharmaceutical Sciences, Kyushu University 62, 3- 1- 1 Maidashi , Higashiku, Fukuok a 812- 82, Japan Institut e of Commun ity Medicine, University of Tsukuba, Tsukuba , Ibaraki 305, Japan Department of Molecular and Medical Pharmacology, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90024, USA Department of Food and Nutrition, Nakamura Gakuen University, 5- 7- 1 Befu, Johnan-ku, Fukuoka 814- 01, Japan

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Abstract

1. The cytochrome P450 isozymes involved in the deamination of amphetamine (AP) andbenzphetamine (BZP) have been studied in liver microsomes from rabbit and rat using isozyme-specific inhibitors. 2. Metabolism ofBZP in ratyielding phenylacetone and formaldehyde was moderately inhibited by testosterone and chloramphenicol. N -Debenzylation was thought tobe P450- dependent, but all inhibitors except for a non-specific inhibitor, SKF-525A, failed to inhibit this reaction. 3. In rabbit, quinidine and testosterone were potent inhibitors of both BZP de amination and dealkylation. Deamination of AP in rabbit was extensively inhibited only with quinidine. 4. AP eamination with purified rabbit CYP2C3, which was previously identified as the major isozyme responsible for this metabolism, was extensively inhibited with quinidine, previously thought to be a specific inhibitor of CYP2D. 5. These results strongly support the notionthatthe CYP2C isozymes playamajorrole in the deamination of both AP and BZP, but not for N -debenzylation of BZP in rat. However, on the basis of different sensitivities toward inhibitors, multiple isozymes seem to be involved in BZP deaminations in both species.

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Major role of the CYP2Cisozymes in deamination of amphetamine and benzphetamine : evidence for the quinidine- specific inhibition of the reactions catalysed by rabbit enzyme

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Major role of the CYP2Cisozymes in deamination of amphetamine and benzphetamine : evidence for the quinidine- specific inhibition of the reactions catalysed by rabbit enzyme

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