ABSTRACT
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.
Subject(s)
Steroids/biosynthesis , Adult , Carbon Radioisotopes , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Glucuronates/urine , Humans , Hydrocortisone/urine , Indicators and Reagents , Isomerism , Male , Middle Aged , Radioisotope Dilution Technique , TritiumABSTRACT
A method is presented for the chemical synthesis of corticosteroid derivatives containing the 20 alpha, 21-diol and 17 alpha, 20 alpha, 21-triol side chains. The ketol side chains of cortisol, corticosterone, 11-deoxycortisol, and 11-deoxycorticosterone were reduced at C-20 with sodium borohydride in a two-phase system consisting of aqueous calcium chloride and an organic phase of chloroform or ethyl acetate. Stereoselectivity of reduction was 92% alpha-oriented for cortisol and 79% alpha-oriented for 11-deoxycortisol at -27 degrees. The 20 alpha-form diminished relative to the 20 beta-form with increasing temperature. For the 17-deoxy steroids, reduction to the 20 alpha-form was 23% for 11-deoxycorticosterone and 41% for corticosterone. The 20 alpha/20 beta ratios of 17-deoxy steroids were unchanged between 0 degree and -27 degrees. Calcium ions increased the solubility of corticosteroids in the aqueous phase. We propose that calcium ions affect the stereochemistry of reduction by forming a bidentate complex with the side chains of 17 alpha-hydroxy steroids, fixing them in an orientation favorable to 20 alpha-reduction, and by altering the phase partition of the steroids.
Subject(s)
Glucocorticoids/chemical synthesis , Borohydrides , Calcium Chloride , Chemical Phenomena , Chemistry , Corticosterone , Cortodoxone , Desoxycorticosterone , Hydrocortisone , Oxidation-Reduction , Solubility , Stereoisomerism , TemperatureABSTRACT
A procedure is described for the chemical synthesis of steroidal-20-oxo-21-oic acids and -17 alpha(-hydroxy-20-oxo-21-oic acids. Corticosteroid derivatives containing the 20-oxo-21-aldehyde side chain are oxidized with freshly generated silver oxide in dilute aqueous sodium hydroxide.
Subject(s)
Keto Acids/chemical synthesis , Steroids/chemical synthesis , Magnetic Resonance Spectroscopy , Methods , Oxidation-ReductionABSTRACT
Cytosols (post-microsomal supernatants) prepared from rat, hamster and mouse livers oxidized cortisol to 11 beta, 17, 20-trihydroxy-3-oxo-pregn-4-en-21-oic acids. Mouse liver enzymes yielded over 90% 20 alpha-hydroxy epimer from cortisol, 21-dehydrocortisol (11 alpha, 17-dihydroxy-3,20-dioxo-pregn-4-en-21-aldehyde), and 20 alpha-isocortisol (11 alpha, 17, 20 alpha-trihydroxy-3-oxo-pregn-4-en-21-aldehyde). The 20 beta-epimer of isocortisol yielded both 20 alpha- and 20 beta-hydroxy acid. Rat and hamster liver cytosols converted, 21-dehydrocortisol and 20 alpha-isocortisol to both 20 alpha and 20 beta-hydroxy acids, with the former predominant. The hamster enzyme oxidized 20 beta-isocortisol mainly to the 20 beta-hydroxy acid. The results support our conclusion that both 17 alpha-hydroxy and 17-deoxy corticosteroids are oxidized to hydroxy acids by similar pathways and that isosteroids are obligatory intermediates.
