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

Abstract

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