Human hepatic cortisol reductase activities: enzymatic properties and substrate specificities of cytosolic cortisol delta 4-5 beta-reductase and dihydrocortisol-3 alpha-oxidoreductase(s).
The metabolism of cortisol by human liver homogenates has been studied. Cortisol delta 4-reductase and dihydrocortisol-3-oxidoreductase activities were distributed in all subcellular fractions. The products of the soluble enzymes were identified. Cortisol and 5 beta-dihydrocortisol were reduced to 3 alpha,5 beta-tetrahydrocortisol, and 5 alpha-dihydrocortisol was reduced to 3 alpha,5 alpha-tetrahydrocortisol. The soluble enzymes showed a wide range of substrate specificity. The 21 substituted cortisol derivatives were not metabolized. The apparent Km values of cortisol delta 4-5 beta-reductase and dihydrocortisol-3 alpha-oxidoreductase for their substrates (cortisol, 5 alpha-dihydrocortisol, and 5 beta-dihydrocortisol) all ranged from 18 to 27 microM. Dexamethasone inhibited the reduction of all of these substrates and the inhibition was abolished by 21 substitution of the dexamethasone. Testosterone was a competitive inhibitor of the reduction of cortisol, 5 alpha-dihydrocortisol, and 5 beta-dihydrocortisol with a Ki ranging from 11 to 32 microM. NADPH was the preferred cofactor for the cortisol delta 4-5 beta-reductase and dihydrocortisol-3 alpha-oxidoreductase. No end product inhibition was observed.
Iyer
R B
RB
Department of Medicine, New York Medical College, Valhalla 10595.
Binstock
J M
JM
Schwartz
I S
IS
Gordon
G G
GG
Weinstein
B I
BI
Southren
A L
AL
D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000201:enzymology*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013053:Spectrophotometry; D013347:Subcellular Fractions / Q000737:chemistry; D013379:Substrate Specificity / Q000502:physiology; D013739:Testosterone / Q000502:physiology; D014316:Tritium
D014316:Tritium; D013739:Testosterone; D010088:Oxidoreductases; D006913:Hydroxysteroid Dehydrogenases; C067784:dihydrocortisol 3alpha-oxidoreductase; C034519:cortisol delta 4-reductase