Diverse effects of α-/β-estradiol on catalytic activities of human UDP-glucuronosyltransferases (UGT)

β-estradiol (β-E2) and α-estradiol (α-E2) act as an endo- and an exon-estrogen in humans, respectively. There is a structural variation in C17-OH configuration of the two estrogens. UDP-glucuronosyltransferases (UGT) are responsible for termination of activities of a variety of endogenous hormones, clinical drugs, and environmental toxicants. The current study was conducted to investigate the effects of the two estrogens towards catalytic activities of UGTs. It was found that β-E2 could decrease activities of UGT1A9 , − 2B4 and − 2B7, with K i values of a few micro-molars. β-E2 could additionally accelerate the activity of UGT2B17 via promoting enzyme-substrate binding and increasing the turn over number . Comparatively, α-E2 displayed much stronger inhibitory potentials towards UGT2B7 and − 2B4, but showed little influence to UGT1A9 and − 2B17. The K i values for inhibition of UGT2B7 in glucuronidation of different substrates by α-E2 were in a nanomolar range that is only about 1/100–1/50 of β-E2. UGT2B7 structural model was fatherly constructed to explore the mechanism underlying dramatically different inhibition selectivity of the two estrogens. Compared to β-E2, α-E2 formed more hydrophobic and hydrogen-bonded interactions with the residues in the active pocket. It is concluded that the configuration of E2–17-OH determines the inhibitory potentials towards UGTs. The results are useful in better understanding ligand selectivity of UGTs, as well as in further development of α-E2 in health protection.