TY - JOUR
T1 - The regio- and stereo-selectivity of C19 and C21 hydroxysteroid glucuronidation by UGT2B7 and UGT2B11
AU - Jin, Chun Jing
AU - Mackenzie, Peter I.
AU - Miners, John O.
PY - 1997/5/15
Y1 - 1997/5/15
N2 - 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.
AB - 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.
KW - glucuronidation
KW - steroid metabolism
KW - UDP-glucuronosyltransferase
KW - UGT2B11
KW - UGT2B7
UR - http://www.scopus.com/inward/record.url?scp=0031570313&partnerID=8YFLogxK
U2 - 10.1006/abbi.1997.9949
DO - 10.1006/abbi.1997.9949
M3 - Article
C2 - 9169006
AN - SCOPUS:0031570313
SN - 0003-9861
VL - 341
SP - 207
EP - 211
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
IS - 2
ER -