NEW PATHWAYS OF CORTICOSTEROID METABOLISM

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Our goals are to elaborate the details of and evaluate the significance of new pathways of corticosteroid metabolism. We have shown in all species studied, including man, that the ketol side chain is reversibly converted by an isomerase to an aldol configuration that can undergo further changes. Interconversion of the 20Alpha and 20Beta epimeric forms of the aldol is catalyzed by an epimerase. Either epimer is oxidized to the hydroxy acid side chain (cortic acids in man) by aldehyde dehydrogenases or reduced to glycols (cortols and cortolones in man) by aldo reductase. The properties of the enzymes that catalyze these changes, isolated from the livers of hamsters and mice, are being studied in detail in order to develop a basis for understanding how the various pathways of corticosteroid metabolism are controlled and coordinated. In parallel studies in humans, metabolic pathways corresponding to those in animals are inferred from the urinary metabolites derived from intravenously injected precursors. The metabolic and clinicophathological significance in man of the expanded pathways of corticosteroid metabolism are under study. In humans, we will use methods that we have developed in order to study how a variety of physiological conditions affect the urinary excretion of the cortoic acids. We will especiallly study infant and juvenile urine in order to establish what other steroid acid metabolites are excreted, and to isolate and identify them. The physiological fractions of the acid end-products of cortisol metabolism and the aldol intermediates will be evaluated by standard anti-inflammatory assays and by induction of specific enzymes such as tyrosines aminotransferase and glycogen synthetase which are known to respond to glucocorticoids. We will continue our studies of side chain isomerase genetics in the mouse in order to specifically map the gene and to establish its multiplicity. Our intentions are to use these studies as models for possible genetic defects of corticosteroid metabolism in humans.