Biotransformation of 8:2 fluorotelomer alcohol by recombinant human cytochrome P450s, human liver microsomes and human liver cytosol

Abstract

Environmental impactFluorotelomer alcohols (FTOHs) are the precursors of peruoroalkyl acids (PFAAs) which are now considered as global persistent organic pollutants and are therefore the potential source of PFAAs. CYP2C19 that we characterized plays a crucial role in the biotransformation of 8:2 FTOH in the human body to form a more toxic metabolite (8:2 uorotelomer aldehyde). Phase II metabolism (glucuronidation and sulfation) showed higher efficiency than phase I metabolism, which indicates that forming conjugates is the major fate of 8:2 FTOH metabolism. These results will help future epidemiological studies in the assessment of indirect sources of human exposure to PFAAs and potential health risks of uorotelomer alcohols.

Translational Biomedical Informatics and Pharmacometrics Approaches in the Drug Interactions Research

“…The percent of inhibition can be calculated by comparing the metabolism rates with and without an inhibitor. Substrate depletion can also be incubated with individual recombinant enzymes isoforms . Each isozyme contribution is estimated as the percent contribution of each CYP enzyme toward the total human liver microsome CLint via a scaling factor (RAF/ISEF) approach .…”

“…Substrate depletion can also be incubated with individual recombinant enzymes isoforms. 44 Each isozyme contribution is estimated as the percent contribution of each CYP enzyme toward the total human liver microsome CLint via a scaling factor (RAF/ISEF) approach. 45 Recently, due to the success of the cryopreservation of human hepatocytes, 46 the hepatocyte suspension model 47 becomes a new method to estimate fm.…”

Uptake, Translocation, and Metabolism of 8:2 Fluorotelomer Alcohol in Soybean (Glycine max L. Merrill)

“…It has been reported that conjugation is the major metabolic pathway of 8:2 FTOH in human liver microsomes. 20 The increases of GSHconjugated metabolite levels and GST enzyme activities in soybean tissues during the exposure time suggested the importance of conjugation on 8:2 FTOH metabolism. To our knowledge, this is the first study to monitor the conjugated metabolites of 8:2 FTOH in a plant.…”

“…47 In vitro studies have suggested that CYP450 enzymes participate in the oxidation of FTOHs by activating 48 reported that CYP2E1, one subfamily of CYP450, likely catalyzed the initial oxidation of FTOH to the respective aldehyde in isolated rat hepatocytes. Li et al 20 found that among 11 isoforms of human CYP450 studied, only CYP2C19 was capable of catalyzing 8:2 FTOH phase I metabolism. However, in this study, 8:2 FTOH treatment did not change the CYP450 activity in soybean roots significantly (P > 0.05, Figure 4D), which indicated that CYP450 may not be the key enzyme involved in 8:2 FTOH metabolism in soybean.…”

“…In the homologous series of FTOHs, 8:2 FTOH has historically been produced in the largest volume. Degradation of 8:2 FTOH by oxidation in the atmosphere, 9,10 photolysis in aqueous environments, 11 aerobic and anaerobic microbial biodegradation in terrestrial environments, 12−14 and in vivo and in vitro metabolism in animals 15−18 and in humans 19,20 has been reported. The 8:2 FTOH degradation in different matrixes shares some common steps, proceeding via saturated and unsaturated fluorotelomer carboxylic acid intermediates, which are finally oxidized to PFCAs as the terminal products.…”