The stereochemistry of enzymic reduction of 21-dehydrocortisol to cortisol.
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Animals↗
Biomedical subjects
C Monder
Publications and source records attributed to C Monder.
Acidic metabolites. VI. 20 alpha-isosteroids as intermediates in 20 alpha-dihydrosteroid formation.
We have previously shown that human subjects metabolize the 20 beta-epimer of isocortisol (11 beta, 17,20 beta-trihydroxy-3-oxo-pregn-4-en-21-al) to both 20 alpha- and 20 beta-hydroxy steroid end products. In this paper we describe the synthesis of tritium labeled 20 alpha-epimers of isocortisol and isoTHF (3 alpha, 11 beta, 17,20 alpha-tetrahydroxy-5 beta-pregnan-21-al) and their metabolic fate in humans. Both steroids yielded 20 alpha-hydroxy urinary neutral end-products (cortols and cortolones) and no 20 beta-hydroxy epimers. Regeneration of 17-ketols from aldols occurred to a small extent with isoTHF, but not with isocortisol. Isocortisol and isoTHF yielded less cortoic acids than did the corresponding ketols. The results provide further evidence that in man the stereochemistry at C-20 of the end-products of corticosteroid metabolism is determined by the configuration of the aldol at C-20 prior to subsequent metabolic events.
Adult↗
Corticosteroid 11 beta-hydroxysteroid dehydrogenase activities in vertebrate liver.
In this paper, we examine corticosteroid 11 beta-oxidation and 11-reduction as properties of the microsomal 11 beta-hydroxysteroid dehydrogenase complex in vertebrate livers. No hepatic activity in the oxidative direction (11 beta -dehydrogenase) was found in the frog, toad, mud puppy, shark, and bird livers. In contrast, all mammalian livers had active oxidizing enzymes. Latency, defined as microsome-linked activity released by the detergent Triton DF-18, was a property of 11 beta-dehydrogenase in all mammalian livers. Mammal, bird, and dogfish livers reduced 11-dehydrocorticosteroids (11-reductase), while amphibians and bony fish did not. With the exception of rat liver, latency was a property of all the mammalian liver 11-reductases examined.
11-beta-Hydroxysteroid Dehydrogenases↗
Corticosteroid-calcium complexes.
Glucocorticoids and calcium ions are shown to interact to yield a complex with properties that are distinct from those of the reactants. Reaction of steroids with Ca2+ appears to require the dihydroxyacetone side chain, since other structures do not react. Evidence for complex formation are: increased aqueous solubility of cortisol when Ca2+ is added to an aqueous or a biphasic aqueous/chloroform (or ethyl acetate) system; increased rate of migration of cortisol during reversed-phase thin-layer chromatography and HPLC; chromatographic comigration of 45Ca2+ and 3H-labeled cortisol; coprecipitation of 45Ca2+-3H-cortisol complexes. After dissociation of the cortisol-calcium complex, the only steroid recovered was cortisol. By the above criteria, the properties of cortisol were not affected by Sr2+, Ba2+, or Mg2+. The cleavage patterns of cortisol in the mass spectrometer corresponded to that of 11 beta-hydroxyandrostenedione when Ca2+ was present, and to cortisol in its absence. We therefore postulate that the structure of the dihydroxyacetone side chain was transiently altered by Ca2+, resulting in a labile C17-C20 bond. These results support our earlier proposal that the chemical and physico-chemical properties of corticosteroids are modified by calcium ions.
Adrenal Cortex Hormones↗
Cloning of cDNA encoding an NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase in sheep kidney.
11 beta-Hydroxysteroid dehydrogenase (11-HSD) catalyzes the conversion of cortisol to cortisone and corticosterone to 11-dehydrocorticosterone. This activity may be required to confer normal ligand specificity upon the mineralocorticoid receptor. Although an isozyme of 11-HSD was previously isolated from rat liver, a different isozyme is apparently expressed in mineralocorticoid target tissues. We isolated a sheep kidney cDNA clone encoding this isozyme by expression screening using Xenopus oocytes. The cDNA is 1.8 kb in length and encodes a protein of 427 amino acid residues with a predicted M(r) of 46,700. When expressed in oocytes, this enzyme functions as an NAD(+)-dependent 11 beta-hydrogenase with very high affinity for steroids, but it has no detectable reductase activity. It is 37% identical in amino acid sequence to an NAD(+)-dependent isozyme of 17 beta-hydroxysteroid dehydrogenase, but only 20% identical to the NADP(+)-dependent liver isozyme of 11-HSD. It is expressed at high levels in the kidney and adrenal and at lower levels in the colon. The corresponding gene is present in a single copy in the sheep genome. In humans, this gene is a candidate locus for the syndrome of apparent mineralocorticoid excess, a form of hypertension postulated to result from 11-HSD deficiency in mineralocorticoid target tissues.
11-beta-Hydroxysteroid Dehydrogenases↗