GLUCURONIDATION OF CATECHOL ESTROGENS BY EXPRESSED HUMAN UDP-GLUCURONOSYLTRANSFERASES (UGTS) 1A1, 1A3, AND 2B7

Catechol estrogens are major estrogen metabolites in mammals and are t he most potent naturally occurring inhibitors of catecholamine metabol ism. These estrogen compounds have been implicated in carcinogenic act ivity and the 412-hydroxyestradiol concentration has been shown to be elevated in neoplastic human mammary tissue compared to normal human b reast tissue. Three human liver UDP-glucuronosyltransferases, UGT2B7, UGT1A1, and UGT1A3, have been shown to catalyze the glucuronidation of catechol estrogens and lead to their enhanced elimination via urine o r bile. The present study was designed to study the kinetic interactio n of expressed human UGT2B7(Y) or (H), UCT1A1, and UGT1A3 toward 2- an d 4-hydroxycatechol estrogens. cDNAs encoding UGT2B7(Y) or (H), UGT1A1 , and UGT1A3 were expressed in HK293 cells, and cell homogenates or me mbrane preparations were used to determine their glucuronidation abili ty. UGT2B7(Y) reacted with higher efficiency toward 4-hydroxyestrogeni c catechols, whereas UGT1A1 and UGT1A3 showed higher activities toward 2-hydroxyestrogens. UGT2B7(H) catalyzed estrogen catechol glucuronida tion with efficiencies similar to UGT2B7(Y). Flunitrazepam (FNZ), a co mpetitive inhibitor of morphine glucuronidation in hepatic microsomes, competitively inhibited catechol estrogen glucuronidation catalyzed b y UGT2B7(Y), UGT1A1, and UGT1A3. Buprenorphine, an opioid substrate th at reacts at high efficiency with each of these UGTs, was also studied . FNZ competitively inhibited buprenorphine glucuronidation with UGT1A 1 and UGT2B7 but had no inhibitory activity toward UGT1A3. This sugges ts that buprenorphine and 2-hydroxycatechol estrogens react with separ ate active sites of UGT1A3. A catecholamine, norepinephrine, did not i nhibit UGT2B7(Y)-, UGT1A1-, and UGT1A3-catalyzed glucuronidation of ca techol estrogens. These results also suggest that drug-endobiotic inte ractions are possible in humans and may have implication in carcinogen esis. (C) 1998 Society of Toxicology.