Metabolism of dihydrotestosterone in human liver:: Importance of 3α- and 3β-hydroxysteroid dehydrogenase

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