Potent inhibition of tributyltin (TBT) and triphenyltin (TPT) against multiple UDP-glucuronosyltransferases (UGT): A new potential mechanism underlying endocrine disrupting actions. (March 2021)

• Record Type: Journal Article
• Authors: Lv, Hui; Wang, Juanjuan; Wang, Mingying; Shen, Li; Xiao, Ling; Chen, Taijie; Sun, Tingzhe; Li, Wenjuan; Zhu, Liangliang; Zhang, Xiaoke
• Is Part Of: Food and chemical toxicology. Volume 149(2021)
• Publication Date: 2021-03
• Subjects: Tributyltin (TBT) -- Triphenyltin (TPT) -- UDP-glucurpnosyltranseferases (UGT) -- Inhibition of UGT; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2021.112039
• Languages: English
• ISSNs: 0278-6915

Abstract

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 K i values of 0.45 and 0.46 μM, respectively. K i 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. Graphical abstract: Image 1 Highlights: Tributyltin and triphenyltin can potently inhibit the activities of multiple UDP-glucuronosyltransferases (UGT). Tributyltin and triphenyltin act as 2 nM inhibitors of UGT2B15. UGT inhibition acts as a new potential mechanism underlying endocrine disrupting actions of organotin compounds.