Kinetic mechanism of reduction of testosterone by hepatic 5 beta-reductase of chicken and inhibition of the reductase activity by a secosteroid, an azasteroid and glycyrrhetinic acid.
The present studies on initial velocity of testosterone reduction by hepatic 5 beta-reductase (4-en-3-oxosteroid 5 beta-reductase) of chicken and mode of inhibition of the 5 beta-reduction by 5 beta-dihydrotestosterone and NADP+ indicated that the reduction of testosterone occurred after the 5 beta-reductase bound firstly to NADPH and then to testosterone, forming a ternary complex. After 5 beta-reduction, 5 beta-dihydrotestosterone and then NADP+ were liberated from the complex, following a mechanism of "ordered Bi-Bi". Effect of (4R)-5,10-seco-19-norpregna-4,5-diene-3,10,20-trione (a steroidal 5 alpha-reductase-inhibitor or Secosteroid), diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (the other steroidal 5 alpha-reductase-inhibitor or 4-MA), and glycyrrhetinic acid (3 beta-hydroxy-11-oxoolean-12-en-30-oic acid, a 5 beta-reductase-inhibitor) was examined upon the 5 beta-reductase activity by double reciprocal plots. The mode of inhibition against testosterone by 4-MA and glycyrrhetinic acid was found to be competitive, while that by Secosteroid was non-competitive.
Yoshida
M
M
Department of Radiopharmacology, Faculty of Pharmaceutical Sciences, Nagasaki University, Japan.
Kuroki
Y
Y
Kobayashi
E
E
Tamaoki
B
B
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology*; D002645:Chickens; D003600:Cytosol / Q000201:enzymology; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006034:Glycyrrhetinic Acid / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D009249:NADP / Q000378:metabolism; D009649:Norpregnadienes / Q000494:pharmacology*; D010084:Oxidation-Reduction; D013739:Testosterone / Q000378:metabolism*
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D001378:Azasteroids; D009649:Norpregnadienes; D013196:Dihydrotestosterone; D013739:Testosterone; D009249:NADP; C015501:(4R)-5,10-seco-19-norpregna-4,5-diene-3,10,20-trione; C031563:17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D006034:Glycyrrhetinic Acid