Inhibition of UDP-glucuronosyltransferases (UGTs) by bromophenols (BPs)

Feige Wang; Shang Wang; Kai Yang; Yong-Zhe Liu; Kun Yang; Yao Chen; Zhong-Ze Fang

doi:10.1016/j.chemosphere.2019.124645

Inhibition of UDP-glucuronosyltransferases (UGTs) by bromophenols (BPs)

Chemosphere. 2020 Jan:238:124645. doi: 10.1016/j.chemosphere.2019.124645. Epub 2019 Aug 24.

Authors

Feige Wang¹, Shang Wang¹, Kai Yang², Yong-Zhe Liu², Kun Yang², Yao Chen³, Zhong-Ze Fang⁴

Affiliations

¹ Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, 300070, China.
² Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China; National Demonstration Center for Experimental Preventive Medicine Education, Tianjin Medical University, Tianjin, 300070, China; Tianjin Center for International Collaborative Research in Environment, Nutrition and Public Health, Tianjin, China.
³ Shenyang Mental Health Center, Shenyang, Liaoning Province, China.
⁴ Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China; National Demonstration Center for Experimental Preventive Medicine Education, Tianjin Medical University, Tianjin, 300070, China; Tianjin Center for International Collaborative Research in Environment, Nutrition and Public Health, Tianjin, China. Electronic address: fangzhongze@tmu.edu.cn.

PMID: 31472352
DOI: 10.1016/j.chemosphere.2019.124645

Abstract

Bromophenols (BPs) are important organic compounds which have become dominant pollutants during these years. Our present study investigated the potential inhibition behaviour of BPs on the activity of one of the most important phase II drug-metabolizing enzymes (DMEs), UDP-glucuronosyltransferases (UGTs). Recombinant UDP-glucuronosyltransferases (UGTs)-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was utilized as the probe reaction. 100 μM of BPs was utilized as the inhibition screening concentrations, and the complete inhibition profile of UGT isoforms by BPs was obtained. UGT1A7 was the most vulnerable UGT isoform towards BPs. Some structure-activity relationship for the inhibition of UGTs by BPs was found, and this relationship can be furtherly explained by the hydrophobic contacts of BPs with the activity cavity of UGTs using in silico docking method. The inhibition kinetics determination showed that the inhibition kinetic parameter K_i value was calculated to be 2.85, 3.99 and 31.00 μM for the inhibition of UGT1A3, UGT1A7, and UGT2B7 by representative BPs, 2,4,6-TBP. Combined with in vivo exposure concentration of 2,4,6-TBP, in vitro-in vivo extrapolation (IVIVE) was employed to demonstrate the moderate possibility for the inhibition of UGT1A3 and UGT1A7 by 2,4,6-TBP. In conclusion, our study gave the full description towards the inhibition of BPs towards UGT isoforms, which will provide a new perspective for elucidating the toxicity mechanism of bromophenols (BPs).

Keywords: Bromine substituent; Bromophenols (BPs); Human UDP-Glucuronosyltransferases (UGTs); Inhibition; In vitro-in vivo extrapolation (IVIVE).

MeSH terms

Catalysis
Glucuronosyltransferase / antagonists & inhibitors*
Glucuronosyltransferase / metabolism
Humans
Hydrocarbons, Brominated / pharmacology*
Hydrophobic and Hydrophilic Interactions
Kinetics
Molecular Docking Simulation
Phenols / pharmacology*
Protein Isoforms / metabolism
Structure-Activity Relationship

Substances

Hydrocarbons, Brominated
Phenols
Protein Isoforms
Glucuronosyltransferase