Identification and characterization of in vitro inhibitors against UDP-glucuronosyltransferase 1A1 in uva-ursi extracts and evaluation of in vivo uva-ursi-drug interactions. (October 2018)

• Record Type: Journal Article
• Authors: Park, Jung Bae; Kim, Doyun; Min, Jee Sun; Jeong, Su; Cho, Doo-Yeoun; Zheng, Yu Fen; Yoon, Kee Dong; Bae, Soo Kyung
• Is Part Of: Food and chemical toxicology. Volume 120(2018)
• Page Start: 651
• Page End: 661
• Publication Date: 2018-10
• Subjects: Uva-ursi extract -- In vitro UGT1A1 inhibition -- Gallotannin -- 1, 2, 3, 6-Tetragalloylglucose -- In vivo herb‒drug interaction; UGT UDP-glucuronosyltransferase -- TeGG 1, 2, 3, 6-tetragalloylglucose -- 4-MU 4-methylumbelliferone -- UDPGA uridine 5′-diphosphoglucuronic acid -- IC50 the 50% inhibitory concentration -- Ki inhibitory constant -- AUC area under concentration-time curve; 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.2018.07.058
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Uva-ursi leaf is widely used to treat symptoms of lower urinary tract infections. Here, we evaluated the in vitro inhibitory effects of uva-ursi extracts on 10 major human UDP-glucuronosyltransferases (UGT) isoforms. Of the 10 tested UGT isoforms, uva-ursi extracts exerted the strongest inhibitory effect on UGT1A1-mediated β-estradiol 3-glucuronidation with the lowest IC50 value of 8.45 ± 1.56 μg/mL. To identify the components of uva-ursi extracts showing strong inhibitory effects against UGT1A1, the inhibitory effects of nine major constituents of the extracts were assessed. Among the tested compounds, gallotannin exerted the most potent inhibition on UGT1A1, followed by 1, 2, 3, 6-tetragalloylglucose; both demonstrated competitive inhibition, with Ki values of 1.68 ± 0.150 μM and 3.55 ± 0.418 μM. We found that gallotannin and 1, 2, 3, 6-tetragalloylglucose also inhibited another UGT1A1-specific biotransformation, SN-38-glucuronidation, showing the same order of inhibition. Thus, in vitro UGT1A1 inhibitory potentials of uva-ursi extracts might primarily result from the inhibitory activities of gallotannin and 1, 2, 3, 6-tetragalloylglucose present in the extracts. However, in rats, co-administration with uva-ursi extracts did not alter the in vivo marker for UGT1A1 activity, expressed as the molar ratio of AUCSN-38 glucuronide /AUCSN-38, because plasma concentrations of gallotannin and 1, 2, 3, 6-tetragalloylglucose may be too low to inhibit the UGT1A1-mediated metabolism of SN-38 in vivo . The poor oral absorption of gallotannin and 1, 2, 3, 6-tetragalloylglucose in uva-ursi extracts might cause the poor in vitro - in vivo correlation. These findings will be helpful for the safe and effective use of uva-ursi extracts in clinical practice. Highlights: Uva-ursi is widely used to treat urinary tract infections. There is no information regarding inhibition of UGTs by uva-ursi. Strong UGT1A1 inhibition by uva-ursi in vitro is attributable to its two constituents, gallotannin and TeGG. But, uva-ursi did not affect UGT1A1 in vivo due to their poor oral absorption.