Metabolism of 11-oxygenated steroids. 2. 2-Methyl steroids

Abstract

The metabolism of 2[alpha]-methylcortisone, 2[alpha]-methylcortisol and 2[alpha]-methyladrenosterone was compared with that of cortisone and adrenosterone after oral administration to young men, with special reference to oxidation-reduction of the 11-oxygen function of these steroids. The 2[alpha]-methyl steroids showed 4 main features of interest: There was an almost complete lack of metabolites reduced in ring A; there was a much higher proportion of 6[beta]-hydroxy and 20[xi]-hydroxy metabolites; there was an inhibition of the usual interconver-sion of 11-ketones and 11[beta]-alcohols, which was far more complete with 2[alpha]-methylcortisone than with 2[alpha]-methyladrenosterone and, despite the lack of 3[alpha]-hydroxy metabolites, at least 98% of the recognized metabolites were in conjugated form. The extent of reduction of the 11-oxo-groups of the precursors suggested by the pattern of urinary metabolites was paralleled in each case by the 11-ketone/11[beta]-alcohol ratio in plasma collected up to 3 hr. after taking each precursor. Furthermore, there was little oxidation of the 11[beta]-hydroxyl group of 2[alpha]-methylcortisol. Arguments are given suggesting that association of 11-oxo steroids with the 11[beta]-dehydrogenase occurs with the steroid tilted on the active region of the enzyme, so that contact is mainly over the [alpha]-surface of the molecule in the region of carbon atoms 1, 2, 11, 12, 17 and 21. The exceptionally high ratio of biological activities of 2[alpha]-methylcortisol and 2[alpha]-methylcortisone appears to be correlated with the exceptionally poor reduction of the latter to the former. It is concluded that biological activity of the 11-oxygenated adrenal steroids is confined to the 11[beta]-hydroxy forms, except when the 11-ketones can be reduced to the former, and that the oxidation-reduction of the 11-oxygen function occurring with the natural adrenal hormones of this type is not directly involved in their mode of action. Alternative theories are discussed.