Emerging investigator series: human CYP2A6 catalyzes the oxidation of 6:2 fluorotelomer alcohol
| Autor: | Oluwadamilola Daramola, Amy A. Rand |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Fluorotelomer alcohol
010501 environmental sciences Management Monitoring Policy and Law 030226 pharmacology & pharmacy 01 natural sciences Cytochrome P-450 CYP2A6 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cytochrome P-450 Enzyme System Biotransformation Animals Humans Environmental Chemistry CYP2A6 0105 earth and related environmental sciences chemistry.chemical_classification Ethanol biology Public Health Environmental and Occupational Health Cytochrome P450 General Medicine Metabolism Enzyme chemistry Biochemistry Microsomes Liver biology.protein Microsome Xenobiotic Oxidation-Reduction |
| Zdroj: | Environmental Science: Processes & Impacts. 23:1688-1695 |
| ISSN: | 2050-7895 2050-7887 |
| Popis: | The biotransformation of 6:2 fluorotelomer alcohol (6:2 FTOH) results in the production of bioactive and persistent metabolites, including perfluorinated carboxylic acids (PFCAs). While the products of 6:2 FTOH metabolism have been elucidated in several animal models, the responsible cytochrome P450 (CYP) isoform(s) have not been reported. Here, we characterized the in vitro oxidation of 6:2 FTOH using human liver microsomes and recombinant human CYPs. Six major xenobiotic metabolizing CYPs were screened for their capacity to catalyze 6:2 FTOH oxidation using chemical inhibitors selective towards CYP isoforms. Of the CYP isoforms investigated, CYP2A6 was the only enzyme capable of catalyzing 6:2 FTOH in human liver microsomes, with KM and Vmax values of 4076 ng mL-1 and 69 ng mL-1 min-1, respectively. We further probed the metabolic mechanism by plotting the 6:2 FTOH kinetic profile and extrapolating data to several possible kinetic models. 6:2 FTOH oxidation followed the typical one-site Michaelis-Menten kinetic model. This study also reports that 6:2 FTOH loss is associated with active CYP2A6 by incubating microsomes with the selective CYP2A6 inhibitor tranylcypromine, which bound competitively to the enzyme as determined by an increased KM (8796 ng mL-1) but unchanged Vmax value. Collectively, these findings provide a mechanistic perspective on the potential importance of CYP2A6 in the metabolic activation and phase I elimination of 6:2 FTOH and indirect human exposure to PFCAs. |
| Databáze: | OpenAIRE |
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