HUMAN HEPATIC CORTISOL REDUCTASE ACTIVITIES - ENZYMATIC-PROPERTIES AND SUBSTRATE SPECIFICITIES OF CYTOSOLIC CORTISOL DELTA-4-5-BETA-REDUCTASE AND DIHYDROCORTISOL-3-ALPHA-OXIDOREDUCTASE(S)

被引:22
作者
IYER, RB [1 ]
BINSTOCK, JM [1 ]
SCHWARTZ, IS [1 ]
GORDON, GG [1 ]
WEINSTEIN, BI [1 ]
SOUTHREN, AL [1 ]
机构
[1] NEW YORK MED COLL,DEPT MED,VALHALLA,NY 10595
关键词
STEROIDS; REDUCTASES; HEPATIC REDUCTASES; CORTISOL;
D O I
10.1016/0039-128X(90)90087-R
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-mu-M. 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 K(i) ranging from 11 to 32-mu-M. NADPH was the preferred cofactor for the cortisol DELTA-4-5-beta-reductase and dihydrocortisol-3-alpha-oxidoreductase. No end product inhibition was observed.
引用
收藏
页码:495 / 500
页数:6
相关论文
共 36 条
  • [21] Zumoff, Bradlow, Gallagher, Hellman, Cortisol metabolism in cirrhosis, J Clin Invest, 46, pp. 1735-1743, (1967)
  • [22] Tomkins, The enzymatic reduction of Δ<sup>4</sup>-3-ketosteroids, J Biol Chem, 225, pp. 13-24, (1957)
  • [23] Forchielli, Dorfman, Separation of Δ<sup>4</sup>-5ga- and Δ<sup>4</sup> 5β-hydrogenases from rat liver homogenates, J Biol Chem, 213, pp. 443-447, (1956)
  • [24] Yates, Herbst, Urquhart, Sex difference in rate of ring A reduction of Δ<sup>4</sup>-3-ketosteroids in vitro by rat liver, Biochem J, 63, pp. 887-902, (1958)
  • [25] Mode, Rafter, The sexually differentiated Δ<sup>4</sup>-3-ketosteroid 5β-reductase of rat liver, J Biol Chem, 260, pp. 7137-7141, (1985)
  • [26] McGuire, Tomkins, The effects of thyroxin administration on the enzymic reduction of Δ<sup>4</sup>-3-kctosteroids, J Biol Chem, 234, pp. 791-794, (1959)
  • [27] Tomkins, A mammalian 3α-hydroxysteroid dehydrogenase, J Biol Chem, 218, pp. 437-447, (1956)
  • [28] Koerner, Assay and substrate specificity of liver 11β-hydroxysteroid dehydrogenase, Biochim Biophys Acta, 176, pp. 377-382, (1969)
  • [29] McGuire, Hollis, Tomkins, Some characteristics of the microsomal steroid reductases (5α) of rat liver, J Biol Chem, 235, pp. 3112-3117, (1960)
  • [30] Okuda, Okuda, Purification and characterization of Δ<sup>4</sup>-3-ketosteroid 5β-reductase, J Biol Chem, 259, pp. 7519-7524, (1985)