Polyfluoroalkyl substance (PFAS) are a family of man-made chemicals typically composed of a fluorinated carbon chain, where the chain length as well as the functional head groups are variable depending on the specific PFAS.  Human dietary exposure to PFAS is a raising concern as they have been detected in food contact material (FCMs). The relationship between PFAS, specifically PFOA and PFOS, and liver toxicity has been well established. Remarkably, little is known about the other emerging PFASs, their metabolic fate and the underlying molecular mechanism leading to their hepatotoxic effect. However, the inhibition of human hepatic cytochrome P450 (CYP) isoenzymes by PFAS has been suggested to play a role. The aim of the present project is therefore to investigate the structure-activity relationship of thirteen PFASs (based on different chain-lengths and functional head-groups) and the interaction with CYP3A4, CYP2C19, CYP2D6 and CYP2E1.

The Vivid® CYP450 Screening Kits from life technologie™ was employed to determine the IC50 for each PFAS and CYP combination. We found that multiple PFAS could inhibit CYP. Specifically, perfluorobutanoic sulfonate, perfluorohexanoic acid, perfluorohexanoic sulfonate, perfluoroheptanoic acid, perfluorononanoic acid, and perfluorodecanoic acid were found to inhibit CYP3A4, 2C19, and 2D6. Perfluorobutanol, perfluorohexanol, and perfluorooctanol, only inhibited CYP2E1.

Interestingly, other PFASs increased CYP2E1 activity. In general, PFAS possessing sulfonic head-groups were more potent inhibitor than their carboxylic counterpart, while PFAS with alcoholic head-groups resulted in no inhibitions except for CYP2E1. Furthermore, PFAS inhibitory potential seemed to increase with the length of their carbon-chain.

In conclusion, our result gave a better insight into the relationship between the structure of PFASs and their interaction with CYP isoenzymes, which may be involved in their hepatotoxic effects. Additionally, we also uncovered a potential adverse outcome pathway for FTMOHs. Indeed, increase of CYP2E1 activity is part of an adverse outcome pathway leading to liver cancer.