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Divisions of Endocrinology and Metabolism (R.J.A.) and Nutrition and Metabolic Diseases (A.K.A.), Department of Internal Medicine, The Donald W. Reynolds Cardiovascular Clinical Research Center (R.J.A.), and the Center for Human Nutrition (A.K.A.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-8857
Address all correspondence and requests for reprints to: Richard J. Auchus, M.D., Ph.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8857. E-mail: richard.auchus{at}UTSouthwestern.edu.
Hydroxysteroid dehydrogenases (HSDs) interconvert potent and relatively inactive forms of individual steroid hormones using nicotinamide cofactors NADPH/NADP+ and NADH/NAD+ [nicotinamide adenine dinucleotide (phosphate), reduced/oxidized forms]. Although reactions with purified enzymes in vitro may be driven in either direction depending on the assay conditions, HSD enzymes appear to function in one direction or the other in intact cells. At least for some of these enzymes, however, the apparent unidirectional metabolism actually reflects bidirectional catalysis that reaches a pseudoequilibrium state with a strong directional preference. This directional preference, in turn, derives from intracellular concentration gradients for the nicotinamide cofactors and the relative affinities of each HSD for these cofactors. Because the concentrations of free cofactor exceed those of steroids by many orders of magnitude, the activities of these enzymes are predominantly driven by cofactor abundance, which is linked to intermediary metabolism. Consequently, the amount of active steroids in cells containing HSDs may be modulated by cofactor abundance and, hence, intracellular redox state. We will review the evidence linking cofactor handling and HSD activity, speculate on additional ways that intracellular metabolism can alter HSD activity and, thus, hormone potency, and discuss fruitful avenues of further investigation.
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