Per- and polyfluoroalkyl substances exert strong inhibition towards human carboxylesterases

Yong-Zhe Liu; Li-Hua Pan; Yu Bai; Kun Yang; Pei-Pei Dong; Zhong-Ze Fang

doi:10.1016/j.envpol.2020.114463

Per- and polyfluoroalkyl substances exert strong inhibition towards human carboxylesterases

Environ Pollut. 2020 Aug;263(Pt A):114463. doi: 10.1016/j.envpol.2020.114463. Epub 2020 Apr 4.

Authors

Yong-Zhe Liu¹, Li-Hua Pan², Yu Bai³, Kun Yang¹, Pei-Pei Dong⁴, Zhong-Ze Fang⁵

Affiliations

¹ 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, 300070, China; National Demonstration Center for Experimental Preventive Medicine Education, Tianjin Medical University, Tianjin, 300070, China; Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin, 300070, China.
² Department of Pharmacy, Tianjin Xiqing Hospital, Tianjin, 300000, China.
³ Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, 300070, China.
⁴ College of Pharmacy, College (Institute) of Integrative Medicine, Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China.
⁵ 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, 300070, China; National Demonstration Center for Experimental Preventive Medicine Education, Tianjin Medical University, Tianjin, 300070, China; Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin, 300070, China. Electronic address: fangzhongze@tmu.edu.cn.

PMID: 32283456
DOI: 10.1016/j.envpol.2020.114463

Abstract

PFASs are highly persistent in both natural and living environment, and pose a significant risk for wildlife and human beings. The present study was carried out to determine the inhibitory behaviours of fourteen PFASs on metabolic activity of two major isoforms of carboxylesterases (CES). The probe substrates 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) for CES1 and fluorescein diacetate (FD) for CES2 were utilized to determine the inhibitory potentials of PFASs on CES in vitro. The results demonstrated that perfluorododecanoic acid (PFDoA), perfluorotetradecanoic acid (PFTA) and perfluorooctadecanoic acid (PFOcDA) strongly inhibited CES1 and CES2. The half inhibition concentration (IC₅₀) value of PFDoA, PFTA and PFOcDA for CES1 inhibition was 10.6 μM, 13.4 μM and 12.6 μM, respectively. The IC₅₀ for the inhibition of PFDoA, PFTA and PFOcDA towards CES2 were calculated to be 9.56 μM, 17.2 μM and 8.73 μM, respectively. PFDoA, PFTA and PFOcDA exhibited noncompetitive inhibition towards both CES1 and CES2. The inhibition kinetics parameters (K_i) were 27.7 μM, 26.9 μM, 11.9 μM, 4.04 μM, 29.1 μM, 27.4 μM for PFDoA-CES1, PFTA-CES1, PFOcDA-CES1, PFDoA-CES2, PFTA-CES2, PFOcDA-CES2, respectively. In vitro-in vivo extrapolation (IVIVE) predicted that when the plasma concentrations of PFDoA, PFTA and PFOcDA were greater than 2.77 μM, 2.69 μM and 1.19 μM, respectively, it might interfere with the metabolic reaction catalyzed by CES1 in vivo; when the plasma concentrations of PFDoA, PFTA and PFOcDA were greater than 0.40 μM, 2.91 μM, 2.74 μM, it might interfere with the metabolic reaction catalyzed by CES2 in vivo. Molecular docking was used to explore the interactions between PFASs and CES. In conclusion, PFASs were found to cause inhibitory effects on CES in vitro, and this finding would provide an important experimental basis for further in vivo testing of PFASs focused on CES inhibition endpoints.

Keywords: Carboxylesterases; Inhibition; Kinetics; Molecular docking simulations; Per- and polyfluoroalkyl substances.

MeSH terms

Carboxylesterase*
Carboxylic Ester Hydrolases*
Humans
Molecular Docking Simulation
Protein Isoforms

Substances

Protein Isoforms
Carboxylic Ester Hydrolases
CES2 protein, human
Carboxylesterase