Mechanistic insights into the specificity of human cytosolic sulfotransferase 2A1 (hSULT2A1) for hydroxylated polychlorinated biphenyls through the use of fluoro-tagged probes

• Published in: Environmental science and pollution research international 2016-02, Vol.23 (3), p.2119-2127
• Main Authors: Ekuase, E. J, van ‘t Erve, T. J, Rahaman, A, Robertson, L. W, Duffel, M. W, Luthe, G
• Format: Article
• Language: English
• Subjects: Aquatic Pollution; Atmospheric Protection/Air Quality Control/Air Pollution; Bioaccumulation; Chemical properties; Earth and Environmental Science; Ecotoxicology; Effects; Environment; Environmental Chemistry; Environmental Health; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme kinetics; Enzymes; Fluorine; Human exposure; Humans; Hydroxylation; in vitro studies; Investigations; Metabolism; Metabolites; PCB; PCBs: Exposures; physicochemical properties; Pollutants; Pollution studies; Polychlorinated biphenyls; Polychlorinated Biphenyls - chemistry; Polychlorinated Biphenyls - metabolism; prediction; Quantitative Structure-Activity Relationship; quantitative structure-activity relationships; Remediation and Regulation with special reference to PCBs in Schools; Substrates; Sulfotransferases - chemistry; Sulfotransferases - metabolism; Toxicity; Toxicology; Waste Water Technology; Water Management; Water Pollution Control; Xenobiotics
• ISSN: 0944-1344; 1614-7499
• DOI: 10.1007/s11356-015-4886-8

Determining the relationships between the structures of substrates and inhibitors and their interactions with drug-metabolizing enzymes is of prime importance in predicting the toxic potential of new and legacy xenobiotics. Traditionally, quantitative structure activity relationship (QSAR) studies are performed with many distinct compounds. Based on the chemical properties of the tested compounds, complex relationships can be established so that models can be developed to predict toxicity of novel compounds. In this study, the use of fluorinated analogues as supplemental QSAR compounds was investigated. Substituting fluorine induces changes in electronic and steric properties of the substrate without substantially changing the chemical backbone of the substrate. In vitro assays were performed using purified human cytosolic sulfotransferase hSULT2A1 as a model enzyme. A mono-hydroxylated polychlorinated biphenyl (4-OH PCB 14) and its four possible mono-fluoro analogues were used as test compounds. Remarkable similarities were found between this approach and previously published QSAR studies for hSULT2A1. Both studies implicate the importance of dipole moment and dihedral angle as being important to PCB structure in respect to being substrates for hSULT2A1. We conclude that mono-fluorinated analogues of a target substrate can be a useful tool to study the structure activity relationships for enzyme specificity.