The Regio- and Stereo-Selectivity of C19 and C21 Hydroxysteroid Glucuronidation by UGT2B7 and UGT2B11

The capacity of two human hepatic UDP-glucuronosyltransferase (UGT) isoforms, UGT2B7 and UGT2B11, to metabolize more than 50 hydroxylated androgens and pregnanes was investigated. All mono- and dihydroxylated androgens with a hydroxyl function in the 3α, 6α, and 17β positions were glucuronidated by UGT2B7, but highest activity was generally observed for steroids containing a 3α-hydroxy substituent. UGT2B7 did not glucuronidate 2α-, 2β-, 3β-, 6β-, 7α-, 11α-, and 11β-monohydroxylated androgens, although the presence of hydroxyl groups at certain of these positions did not abolish the ability of UGT2B7 to metabolize diols which also possessed a 3α- or 17β-hydroxyl group. 3α-Hydroxypregnanes were also glucuronidated by UGT2B7. Activity was not detected for 6α-, 6β-, 11β-, 12α-, 16α-, 17α-, 20α-, or 21-monohydroxylated pregnanes. Although 11α-hydroxylated androgens were not glucuronidated by UGT2B7, this enzyme exhibited high activity toward the 11α-hydroxylated derivatives of 5β-prenanedione and progesterone. UGT2B11 similarly glucuronidated 3α-hydroxyandrogens and -pregnanes, but rates of metabolism were low compared to UGT2B7. With the exception of androsterone and its 5β-isomer, ring A/B stereochemistry appeared not to influence rates of hydroxysteroid glucuronidation by UGT2B7 and UGT2B11. Overall, the data indicate a high degree of stereo- and regioselectivity in the glucuronidation of hydroxyandrogens and -pregnanes by UGT2B7 and UGT2B11 and further suggest that UGT2B7 may contribute to the glucuronidation of 3α-hydroxysteroids in humans.