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Research ArticleArticle

Cloning and Characterization of Four Rabbit Aldo-Keto Reductases Featuring Broad Substrate Specificity for Xenobiotic and Endogenous Carbonyl Compounds: Relationship with Multiple Forms of Drug Ketone Reductases

Satoshi Endo, Toshiyuki Matsunaga, Yuki Arai, Akira Ikari, Kazuo Tajima, Ossama El-Kabbani, Shigeru Yamano, Akira Hara and Yukio Kitade
Drug Metabolism and Disposition April 2014, 42 (4) 803-812; DOI: https://doi.org/10.1124/dmd.113.056044
Satoshi Endo
Gifu Pharmaceutical University, Gifu, Japan (S.E., T.M., Y.A., A.I.); Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan (K.T.); Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia (O.E.); Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan (S.Y.); and Faculty of Engineering (A.H., Y.K.), Gifu University, Gifu, Japan
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Toshiyuki Matsunaga
Gifu Pharmaceutical University, Gifu, Japan (S.E., T.M., Y.A., A.I.); Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan (K.T.); Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia (O.E.); Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan (S.Y.); and Faculty of Engineering (A.H., Y.K.), Gifu University, Gifu, Japan
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Yuki Arai
Gifu Pharmaceutical University, Gifu, Japan (S.E., T.M., Y.A., A.I.); Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan (K.T.); Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia (O.E.); Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan (S.Y.); and Faculty of Engineering (A.H., Y.K.), Gifu University, Gifu, Japan
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Akira Ikari
Gifu Pharmaceutical University, Gifu, Japan (S.E., T.M., Y.A., A.I.); Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan (K.T.); Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia (O.E.); Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan (S.Y.); and Faculty of Engineering (A.H., Y.K.), Gifu University, Gifu, Japan
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Kazuo Tajima
Gifu Pharmaceutical University, Gifu, Japan (S.E., T.M., Y.A., A.I.); Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan (K.T.); Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia (O.E.); Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan (S.Y.); and Faculty of Engineering (A.H., Y.K.), Gifu University, Gifu, Japan
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Ossama El-Kabbani
Gifu Pharmaceutical University, Gifu, Japan (S.E., T.M., Y.A., A.I.); Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan (K.T.); Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia (O.E.); Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan (S.Y.); and Faculty of Engineering (A.H., Y.K.), Gifu University, Gifu, Japan
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Shigeru Yamano
Gifu Pharmaceutical University, Gifu, Japan (S.E., T.M., Y.A., A.I.); Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan (K.T.); Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia (O.E.); Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan (S.Y.); and Faculty of Engineering (A.H., Y.K.), Gifu University, Gifu, Japan
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Akira Hara
Gifu Pharmaceutical University, Gifu, Japan (S.E., T.M., Y.A., A.I.); Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan (K.T.); Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia (O.E.); Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan (S.Y.); and Faculty of Engineering (A.H., Y.K.), Gifu University, Gifu, Japan
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Yukio Kitade
Gifu Pharmaceutical University, Gifu, Japan (S.E., T.M., Y.A., A.I.); Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan (K.T.); Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia (O.E.); Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan (S.Y.); and Faculty of Engineering (A.H., Y.K.), Gifu University, Gifu, Japan
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Abstract

Multiple forms of reductases for several drug ketones were isolated from rabbit liver, but their interrelationship and physiologic roles remain unknown. We isolated cDNAs for four aldo-keto reductases (AKR1C30, AKR1C31, AKR1C32, and AKR1C33), which share high amino acid sequence identity with the partial sequences of two rabbit naloxone reductases. The four recombinant enzymes reduced a variety of carbonyl compounds, including endogenous α-dicarbonyls (e.g., isatin and diacetyl), aldehydes (e.g., farnesal and 4-oxo-2-nonenal), and ketosteroids. They differed in specificity for drug ketones and ketosteroids. Although daunorubicin and befunolol were common substrates of all of the enzymes, AKR enzymes specifically reduced naloxone (AKR1C30, AKR1C32, and AKR1C33), metyrapone (AKR1C32 and AKR1C33), loxoprofen (AKR1C31 and AKR1C32), ketotifen (AKR1C30), and naltrexone and fenofibric acid (AKR1C33). AKR1C30 reduced only 17-keto-5β-androstanes, whereas the other enzymes were active toward 3-, 17-, and 20-ketosteroids, and AKR1C33 further reduced 3-keto groups of bile acids and 7α-hydroxy-5β-cholestanes. In addition, AKR1C30, AKR1C31, AKR1C32, and AKR1C33 were selectively inhibited by carbenoxolone, baccharin, phenolphthalein, and zearalenone, respectively. The mRNAs for the four enzymes were ubiquitously expressed in male rabbit tissues, in which highly expressed tissues were the brain, heart, liver, kidney, intestine, colon, and testis (for AKR1C30 and AKR1C31); brain, heart, liver, kidney, testis, lung, and adrenal gland (for AKR1C32); and liver and intestine (for AKR1C33). Thus, the four enzymes correspond to the multiple drug ketone reductases, and may function in the metabolisms of steroids, isatin and reactive carbonyl compounds, and bile acid synthesis.

Footnotes

    • Received November 14, 2013.
    • Accepted February 7, 2014.
  • This researched was supported in part by the Japan Society for the Promotion of Science [Grant-in-Aid for Young Scientists (B) 24790114] and the Japan Science Society [Sasakawa Scientific Research Grant 24-413].

  • dx.doi.org/10.1124/dmd.113.056044.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (4)
Drug Metabolism and Disposition
Vol. 42, Issue 4
1 Apr 2014
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Research ArticleArticle

Rabbit Drug Ketone Reductases

Satoshi Endo, Toshiyuki Matsunaga, Yuki Arai, Akira Ikari, Kazuo Tajima, Ossama El-Kabbani, Shigeru Yamano, Akira Hara and Yukio Kitade
Drug Metabolism and Disposition April 1, 2014, 42 (4) 803-812; DOI: https://doi.org/10.1124/dmd.113.056044

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Research ArticleArticle

Rabbit Drug Ketone Reductases

Satoshi Endo, Toshiyuki Matsunaga, Yuki Arai, Akira Ikari, Kazuo Tajima, Ossama El-Kabbani, Shigeru Yamano, Akira Hara and Yukio Kitade
Drug Metabolism and Disposition April 1, 2014, 42 (4) 803-812; DOI: https://doi.org/10.1124/dmd.113.056044
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