Different Effects of Desipramine on Bufuralol 1"-Hydroxylation by Rat and Human CYP2D Enzymes(Pharmacology)

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概要

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• Inhibitory effects of desipramine (DMI) on rat and human CYP2D enzymes were studied using bufuralol (BF) 1"-hydroxylation as an index. Inhibition was examined under the following two conditions : 1) DMI was coincubated with BF and NADPH in the reaction mixture containing rat or human liver microsomes or yeast cell microsomes expressing rat CYP2D1, CYP2D2 or human CYP2D6 (co-incubation) ; 2) DMI was preincubated with NADPH and the same enzyme sources prior to adding the substrate (preincubation). When either rat liver microsomes or recombinant CYP2D2 was employed, the preincubation with DMI (0.3μM) caused a greater inhibition of BF 1"-hydroxylation than the co-incubation did, whereas BF 1"-hydroxylation by rat CYP2D1 was not markedly affected under the same conditions. The inhibitory effect of DMI on BF 1"-hydroxylation by human liver microsomal fractions or recombinant CYP2D6 was much lower than that on the hydroxylation by rat liver microsomes or CYP2D2. Kinetic studies demonstrated that the inhibition-type changed from competitive for the co-incubation to noncompetitive for the preincubation in the case of CYP2D2, whereas the inhibition-type was competitive for both the co-incubation and the preincubation in the case of CYP2D6. Furthermore, the loss of activity of rat CYP2D2 under the preincubation conditions followed pseudo-first-order kinetics. Binding experiments employing the recombinant enzymes and [^3H]-DMI revealed that CYP2D2 and CYP2D6 were the only prominent proteins to which considerable radioactive DMI metabolite(s) bound. These results indicate that rat CYP2D2 biotransforms DMI into reactive metabolite(s), which covalently bind to CYP2D2, resulting in inactivation of the enzyme. In contrast, human CYP2D6 may also biotransform DMI into some metabolite(s) that covalently bind to CYP2D6, but that do not inactivate the enzyme.

• 社団法人日本薬学会の論文
• 2005-04-01

著者

• NARIMATSU Shizuo

  Laboratories of Health Chemistry,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,

• Hichiya Hiroyuki

  Laboratories Of Health Chemistry Okayama University

• Hichiya Hiroyuki

  岡山大学 薬学部薬品構造物性化学

• Yamamoto S

  Fukuoka Univ. Fukuoka Jpn

• FUNAE Yoshihiko

  Laboratory of Chemistry, Osaka City University Medical School

• ISOBE Takashi

  Laboratory of Health Chemistry, Faculty of Pharmaceutical Sciences, Okayama University

• HANIOKA Nobumitsu

  Laboratory of Health Chemistry, Faculty of Pharmaceutical Sciences, Okayama University

• YAMAMOTO Shigeo

  Laboratory of Biomolecular Sciences, Faculty of Pharmaceutical Sciences, Okayama University

• SHINODA Sumio

  Laboratory of Environmental Hygine, Faculty of Pharmaceutical Sciences, Okayama University

• SATOH Tetsuo

  Human Animal Bridge Discussion Group

• YAMANO Shigeru

  Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Fukuoka University

• Shinoda S

  Okayama Univ. Okayama Jpn

• Shinoda Sumio

  Fac. Of Sciences Okayama Univ. Of Sci.

• Funae Yoshihiko

  Laboratory Of Chemistry Osaka City University Medical School

• Funae Yoshihiko

  Laboratory Of Chemistry Osaka City University

• Narimatsu Shizuo

  Laboratories Of Health Chemistry Okayama University

• Narimatsu Shizuo

  Laboratories Health Chemistry Faculty Of Pharmaceutical Sciences Okayama University

• Hanioka Nobumitsu

  Laboratories Of Health Chemistry Okayama University

• Satoh Tetsuo

  Non-profit Organization Human & Animal Bridging Research Institute Ichikawa General Hospital

• Shinoda S

  Fac. Of Sciences Okayama Univ. Of Sci.

• Shinoda Sumio

  Laboratories Of Environmental Hygiene Faculty Of Pharmaceutical Sciences Okayama University

• Shinoda S

  Faculty Of Pharmaceutical Sciences Okayama University

• Isobe Takashi

  Laboratories Of Health Chemistry Okayama University

• Yamamoto Shigeo

  Laboratories Of Biomolecular Sciences Faculty Of Pharmaceutical Sciences Okayama University

• Yamamoto S

  Department Of Pharmacology And Pharmaceutics Graduate School Of Natural Science And Technology Kanaz

• YAMANO SHIGERU

  Department of Chemical Engineering, Gumma University

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