Potent inhibition of tributyltin (TBT) and triphenyltin (TPT) against multiple UDP-glucuronosyltransferases (UGT): A new potential mechanism underlying endocrine disrupting actions

Abstract

Organotin compounds (OTs) act as potent endocrine disruptors that are often found in polluted food and water. UDP-glucuronosyltransferases (UGTs) are responsible for termination of multiple endogenous hormones. This study was conducted to investigate the inhibitory effects of two tri-submitted OTs tributyltin (TBT) and triphenyltin (TPT), against activities of UGTs. It is revealed that TBT and TPT act as two potent inhibitors for multiple UGTs. UGT1A8 and -2B15 were coinhibited by the two OTs. UGT1A1 and -1A10 were inhibited by TPT, whereas UGT 2B4 and -2B7 were inhibited by TBT. Kinetic analyses further indicated that TBT and TPT are two competitive nanomolar inhibitors of UGT2B15, with Ki values of 0.45 and 0.46 μM, respectively. Ki values for the other UGTs are determined to be a few micromolars. In addition, the two OTs displayed effective inhibition against UGT2B15 in catalyzing dihydrotestosterone glucuronidation, with IC50 values both in nano-molar range. TPT can additionally inhibit activities of UGT1A1 and -1A10 in estradiol-3-O-glucuronidation, with IC50 values of a few micro-molars. These results indicated that the two OTs can extensively interfere with glucuronidation of endogenous hormones, which may act as a new potential mechanism resulting in endocrine disrupting actions.