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OtherDRUG METABOLISM AND DISPOSITION

Activation of Human Liver 3α-Hydroxysteroid Dehydrogenase by Clofibrate Derivatives

Kazuya Matsuura, Akira Hara, Makiko Kato, Yoshihiro Deyashiki, Yoshiyuki Miyabe, Syuhei Ishikura, Tadashi Sugiyama and Yoshihiro Katagiri
Journal of Pharmacology and Experimental Therapeutics June 1998, 285 (3) 1096-1103;
Kazuya Matsuura
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Akira Hara
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Makiko Kato
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Yoshihiro Deyashiki
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Yoshiyuki Miyabe
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Syuhei Ishikura
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Tadashi Sugiyama
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Yoshihiro Katagiri
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Abstract

The NADP+-dependent dehydrogenase activity of a predominant isoenzyme of human liver 3α-hydroxysteroid dehydrogenase was activated by antihyperlipidemic drugs, such as bezafibrate and clinofibrate, and by clofibric acid and fenofibric acid (active metabolites of clofibrate and fenofibrate, respectively). The optimal pH of the activation by the drugs was about 7.5, and the concentrations giving maximum stimulation (1.8- to 2.4-fold) were 100, 50, 400 and 50 μM for bezafibrate, clinofibrate, clofibric acid and fenofibric acid, respectively. Clofibrate and fenofibrate acted as weak inhibitors, and the clofibric acid derivatives that lack the chloro group, methyl group on the α-carbon or carboxyl group greatly decreased the stimulatory effects. The activation by the drugs increased bothKm and kcat (turnover number) values for the coenzyme and substrates. Kinetic analysis with respect to NADP+ showed that bezafibrate, clinofibrate, clofibric acid and fenofibric acid were nonessential activators showing dissociation constants of 32, 6, 103 and 11 μM, respectively. The combined activators experiments with one of the above drugs and sulfobromophthalein, a known activator specific for this enzyme, and comparison of their effects on the activities of mutant enzymes (with Met replacing Lys-270 or Arg-276) indicated that sulfobromophthalein and the drugs bind to an identical site on the enzyme. These results suggest that the long-term therapy with the antihyperlipidemic drugs influences the metabolism of steroid hormones, bile acids and several ketone-containing drugs mediated by the enzyme.

Footnotes

  • Send reprint requests to: Dr. Akira Hara, Laboratory of Biochemistry, Gifu Pharmaceutical University, Mitahora-higashi, Gifu, 502-8585 Japan.

  • ↵1 This study was supported by a grant from the Ministry of Education, Science, Sports and Culture of Japan and by Suzuken Memorial Foundation.

  • Abbreviations:
    3αHSD
    3α-hydroxysteroid dehydrogenase
    AKR
    aldo-keto reductase
    K270M
    AKR 1C4 with Met replacing Lys-270
    R276M
    AKR 1C4 with Met replacing Arg-276
    • Received August 29, 1997.
    • Accepted February 9, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 3
1 Jun 1998
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OtherDRUG METABOLISM AND DISPOSITION

Activation of Human Liver 3α-Hydroxysteroid Dehydrogenase by Clofibrate Derivatives

Kazuya Matsuura, Akira Hara, Makiko Kato, Yoshihiro Deyashiki, Yoshiyuki Miyabe, Syuhei Ishikura, Tadashi Sugiyama and Yoshihiro Katagiri
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1096-1103;

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OtherDRUG METABOLISM AND DISPOSITION

Activation of Human Liver 3α-Hydroxysteroid Dehydrogenase by Clofibrate Derivatives

Kazuya Matsuura, Akira Hara, Makiko Kato, Yoshihiro Deyashiki, Yoshiyuki Miyabe, Syuhei Ishikura, Tadashi Sugiyama and Yoshihiro Katagiri
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1096-1103;
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