RT Journal Article
SR Electronic
T1 Activation of Human Liver 3α-Hydroxysteroid Dehydrogenase by Clofibrate Derivatives
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1096
OP 1103
VO 285
IS 3
A1 Kazuya Matsuura
A1 Akira Hara
A1 Makiko Kato
A1 Yoshihiro Deyashiki
A1 Yoshiyuki Miyabe
A1 Syuhei Ishikura
A1 Tadashi Sugiyama
A1 Yoshihiro Katagiri
YR 1998
UL http://jpet.aspetjournals.org/content/285/3/1096.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics