Inhibition of UDP-glucuronosyltransferases (UGTs) by polycyclic aromatic hydrocarbons (PAHs) and hydroxy-PAHs (OH-PAHs). 2020

Qiaoyun Yang, and Yu Bai, and Guo-Qiang Qin, and Ruo-Yong Jia, and Weihua Zhu, and Dafang Zhang, and Zhong-Ze Fang
Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin 300070, PR China; Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, Tianjin 300070, PR China; National Demonstration Center for Experimental Preventive Medicine Education (Tianjin Medical University), Tianjin 300070, PR China.

Polycyclic aromatic hydrocarbons (PAHs) are known as one of the ubiquitous environmental pollutants caused by unavoidable combustion of by-products. Despite decades of research on adverse health effects towards humans, the effects of PAHs and their hydroxylated metabolites (OH-PAHs) on UDP-glucuronosyltransferases (UGTs) remain unclear. This study aimed to investigate inhibitory effects with structure-dependence of 14 PAHs and OH-PAHs towards the activity of 7 isoforms of UGTs using in vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) as the probe reaction. PAHs and OH-PAHs showed inhibitory effects towards different UGT isoforms with different extents. For inhibition kinetics determination, 1-HONAP, 4-HOPHE, 9-HOPHE, and 1-HOPYR were utilized as the representative compounds, and UGT1A6, UGT1A9 and UGT2B7 were chosen as the three representative UGT isoforms. The inhibitory effects of 4-HOPHE, 9-HOPHE and 1-HOPYR on three above UGT isoforms were the same: UGT1A9>UGT1A6>UGT2B; for 1-HONAP, that is UGT1A6>UGT1A9>UGT2B. Molecular docking methods were utilized to find the activity cavity of UGT1A9 and UGT2B7 binding with 1-HONAP and 1-HOPYR. Hydrogen bonds and hydrophobic contacts were mainly contributors to their interactions. In vitro-in vivo extrapolation (IVIVE) showed that high in vivo inhibition possibility exists for the inhibition of OH-PAHs on UGTs. All the results provide a novel viewpoint for an explanation of the toxicity of PAHs and OH-PAHs.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D011084 Polycyclic Aromatic Hydrocarbons Aromatic hydrocarbons that contain extended fused-ring structures. Polycyclic Aromatic Hydrocarbon,Polycyclic Hydrocarbons, Aromatic,Polynuclear Aromatic Hydrocarbon,Polynuclear Aromatic Hydrocarbons,Aromatic Hydrocarbon, Polycyclic,Aromatic Hydrocarbon, Polynuclear,Aromatic Hydrocarbons, Polycyclic,Aromatic Hydrocarbons, Polynuclear,Aromatic Polycyclic Hydrocarbons,Hydrocarbon, Polycyclic Aromatic,Hydrocarbon, Polynuclear Aromatic,Hydrocarbons, Aromatic Polycyclic,Hydrocarbons, Polycyclic Aromatic,Hydrocarbons, Polynuclear Aromatic
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006923 Hymecromone A coumarin derivative possessing properties as a spasmolytic, choleretic and light-protective agent. It is also used in ANALYTICAL CHEMISTRY TECHNIQUES for the determination of NITRIC ACID. Imecromone,Methylumbelliferone,Resocyanine,4-Methylumbelliferone,7-Hydroxy-4-methyl-coumarin,Cholestil,Mendiaxon,4 Methylumbelliferone,7 Hydroxy 4 methyl coumarin
D014453 Glucuronosyltransferase A family of enzymes accepting a wide range of substrates, including phenols, alcohols, amines, and fatty acids. They function as drug-metabolizing enzymes that catalyze the conjugation of UDPglucuronic acid to a variety of endogenous and exogenous compounds. EC 2.4.1.17. Glucuronyltransferase,UDP Glucuronosyltransferase,17 beta-Hydroxysteroid UDP-Glucuronosyltransferase,4-Nitrophenol-UDP-Glucuronosyltransferase,7-Hydroxycoumarin UDP Glucuronyltransferase,Androsterone UDP-Glucuronosyltransferase,Bilirubin UDP-Glucuronyltransferase,Estrogen UDP-Glucuronosyltransferase,Estrone Glucuronyltransferase,Glucuronic Transferase,Morphine Glucuronyltransferase,UDP Glucuronyl Transferase,UDP-Glucuronic Acid 3-O-beta-D-Galactosyl-D-Galactose Glucuronosyltransferase,p-Nitrophenyl UDP-Glucuronosyltransferase,17 beta Hydroxysteroid UDP Glucuronosyltransferase,4 Nitrophenol UDP Glucuronosyltransferase,7 Hydroxycoumarin UDP Glucuronyltransferase,Androsterone UDP Glucuronosyltransferase,Bilirubin UDP Glucuronyltransferase,Estrogen UDP Glucuronosyltransferase,Glucuronosyltransferase, UDP,Glucuronyl Transferase, UDP,Glucuronyltransferase, 7-Hydroxycoumarin UDP,Glucuronyltransferase, Estrone,Glucuronyltransferase, Morphine,Transferase, Glucuronic,Transferase, UDP Glucuronyl,UDP Glucuronic Acid 3 O beta D Galactosyl D Galactose Glucuronosyltransferase,UDP Glucuronyltransferase, 7-Hydroxycoumarin,UDP-Glucuronosyltransferase, 17 beta-Hydroxysteroid,UDP-Glucuronosyltransferase, Androsterone,UDP-Glucuronosyltransferase, Estrogen,UDP-Glucuronosyltransferase, p-Nitrophenyl,UDP-Glucuronyltransferase, Bilirubin,p Nitrophenyl UDP Glucuronosyltransferase
D062105 Molecular Docking Simulation A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein. Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking
D020033 Protein Isoforms Different forms of a protein that may be produced from different GENES, or from the same gene by ALTERNATIVE SPLICING. Isoform,Isoforms,Protein Isoform,Protein Splice Variant,Splice Variants, Protein,Protein Splice Variants,Isoform, Protein,Isoforms, Protein,Splice Variant, Protein,Variant, Protein Splice,Variants, Protein Splice

Related Publications

Qiaoyun Yang, and Yu Bai, and Guo-Qiang Qin, and Ruo-Yong Jia, and Weihua Zhu, and Dafang Zhang, and Zhong-Ze Fang
January 2020, Chemosphere,
Qiaoyun Yang, and Yu Bai, and Guo-Qiang Qin, and Ruo-Yong Jia, and Weihua Zhu, and Dafang Zhang, and Zhong-Ze Fang
April 2018, Chemosphere,
Qiaoyun Yang, and Yu Bai, and Guo-Qiang Qin, and Ruo-Yong Jia, and Weihua Zhu, and Dafang Zhang, and Zhong-Ze Fang
August 2023, Toxicology in vitro : an international journal published in association with BIBRA,
Qiaoyun Yang, and Yu Bai, and Guo-Qiang Qin, and Ruo-Yong Jia, and Weihua Zhu, and Dafang Zhang, and Zhong-Ze Fang
December 2018, Chemosphere,
Qiaoyun Yang, and Yu Bai, and Guo-Qiang Qin, and Ruo-Yong Jia, and Weihua Zhu, and Dafang Zhang, and Zhong-Ze Fang
May 2017, Xenobiotica; the fate of foreign compounds in biological systems,
Qiaoyun Yang, and Yu Bai, and Guo-Qiang Qin, and Ruo-Yong Jia, and Weihua Zhu, and Dafang Zhang, and Zhong-Ze Fang
March 2013, Toxicology and applied pharmacology,
Qiaoyun Yang, and Yu Bai, and Guo-Qiang Qin, and Ruo-Yong Jia, and Weihua Zhu, and Dafang Zhang, and Zhong-Ze Fang
October 2015, Phytotherapy research : PTR,
Qiaoyun Yang, and Yu Bai, and Guo-Qiang Qin, and Ruo-Yong Jia, and Weihua Zhu, and Dafang Zhang, and Zhong-Ze Fang
March 2018, Xenobiotica; the fate of foreign compounds in biological systems,
Qiaoyun Yang, and Yu Bai, and Guo-Qiang Qin, and Ruo-Yong Jia, and Weihua Zhu, and Dafang Zhang, and Zhong-Ze Fang
June 2015, Chirality,
Qiaoyun Yang, and Yu Bai, and Guo-Qiang Qin, and Ruo-Yong Jia, and Weihua Zhu, and Dafang Zhang, and Zhong-Ze Fang
January 2014, Die Pharmazie,
Copied contents to your clipboard!