Metabolism of Dihydrotestosterone in Human Liver: Importance of 3α- and 3β-Hydroxysteroid Dehydrogenase1

This study compared the enzyme activity of 3alpha-hydroxysteroid dehydrogenase (3alphaHSD) and 3beta-hydroxysteroid dehydrogenase (3betaHSD) in the human liver. 3AlphaHSD was found in both microsomal and cytosolic liver fractions. Contrary to that in rat liver, microsomal 3alphaHSD activity was 12-fold higher than cytosolic 3alphaHSD activity, and 3alphaHSD was not inhibited by indomethacin (10 micromol/L). The rate of 5alpha-dihydrotestosterone (DHT) reduction to 5alpha-androstane-3alpha,17beta-diol (3alphaDIOL) by 3alphaHSD was 2 times higher than the rate of 3alphaDIOL oxidation to DHT. 3BetaHSD was present primarily in the microsomal fraction of the human liver, and the rate of DHT reduction to 5alpha-androstane-3beta,17beta-diol (3betaDIOL) by 3betaHSD was 3 times higher than the rate of 3betaHSD oxidation to DHT. When 3alphaHSD and 3betaHSD activities were compared, the rate of DHT reduction by 3betaHSD was 3-fold lower than the rate of DHT reduction by 3alphaHSD. No sex or age differences were found in either 3alphaHSD or 3betaHSD activity. As the activity of DHT-metabolizing enzymes is not sex dependent, the sex differences in plasma levels of 3alphaDIOL glucuronide probably reflect differences in DHT production rather than in DHT metabolism. Comparison of the activities of 3alphaHSD, 3betaHSD, and androgen UDP-glucuronyl transferase suggests that the major pathway of DHT metabolism in human liver involves 3alphaHSD reduction in the liver, followed by subsequent glucuronidation and clearance via the kidney.