Effects of short-chain per- and polyfluoroalkyl substances (PFAS) on human cytochrome P450 (CYP450) enzymes and human hepatocytes: An in vitro study
Short-chain per- and polyfluoroalkyl substances (PFAS) have been developed as alternatives to legacy long-chain PFAS, but they may still pose risks due to their potential to interact with biomolecules. Cytochrome P450 (CYP450) enzymes are essential for xenobiotic metabolism, and disruptions of these...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-01-01
|
| Series: | Current Research in Toxicology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666027X23000142 |
| _version_ | 1797397530392133632 |
|---|---|
| author | Megan E. Solan Ramon Lavado |
| author_facet | Megan E. Solan Ramon Lavado |
| author_sort | Megan E. Solan |
| collection | DOAJ |
| description | Short-chain per- and polyfluoroalkyl substances (PFAS) have been developed as alternatives to legacy long-chain PFAS, but they may still pose risks due to their potential to interact with biomolecules. Cytochrome P450 (CYP450) enzymes are essential for xenobiotic metabolism, and disruptions of these enzymes by PFAS can have significant human health implications. The inhibitory potential of two legacy long-chain (PFOA and PFOS) and five short-chain alternative PFAS (PFBS, PFHxA, HFPO-DA, PFHxS, and 6:2 FTOH) were assessed in recombinant CYP1A2, − 2B6, −2C19, −2E1, and −3A4 enzymes. Most of the short-chain PFAS, except for PFHxS, tested did not result in significant inhibition up to 100 μM. PFOS inhibited recombinant CYP1A2, −2B6, −2C19, and −3A4 enzymes. However, concentrations where inhibition occurred, were all higher than the averages reported in population biomonitoring studies, with IC50 values higher than 10 µM. We also evaluated the activities of CYP1A2 and CYP3A4 in HepaRG monolayers following 48 h exposures of the short-chain PFAS at two concentrations (1 nM or 1 µM) and with or without an inducer (benzo[a]pyrene, BaP, for CYP1A2 and rifampicin for CYP3A4). Our findings suggest that both 1 nM and 1 µM exposures to short-chain PFAS can modulate the CYP1A2 activity induced by BaP. Except for PFHxS, the short-chain PFAS appear to have little effect on CYP3A4 activity. Understanding the effects of PFAS exposure on biotransformation can shed light on the mechanisms of PFAS toxicity and aid in developing effective strategies for managing chemical risks, enabling regulators to make more informed decisions. |
| first_indexed | 2024-03-09T01:11:21Z |
| format | Article |
| id | doaj.art-233c3b2d96684937af959a25f0a5114b |
| institution | Directory Open Access Journal |
| issn | 2666-027X |
| language | English |
| last_indexed | 2024-03-09T01:11:21Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Current Research in Toxicology |
| spelling | doaj.art-233c3b2d96684937af959a25f0a5114b2023-12-11T04:17:09ZengElsevierCurrent Research in Toxicology2666-027X2023-01-015100116Effects of short-chain per- and polyfluoroalkyl substances (PFAS) on human cytochrome P450 (CYP450) enzymes and human hepatocytes: An in vitro studyMegan E. Solan0Ramon Lavado1Department of Environmental Science, Baylor University, Waco, TX 76798, United StatesCorresponding author at: Baylor University, Department of Environmental Science, One Bear Place #97266, Waco, TX 76798-7266, United States.; Department of Environmental Science, Baylor University, Waco, TX 76798, United StatesShort-chain per- and polyfluoroalkyl substances (PFAS) have been developed as alternatives to legacy long-chain PFAS, but they may still pose risks due to their potential to interact with biomolecules. Cytochrome P450 (CYP450) enzymes are essential for xenobiotic metabolism, and disruptions of these enzymes by PFAS can have significant human health implications. The inhibitory potential of two legacy long-chain (PFOA and PFOS) and five short-chain alternative PFAS (PFBS, PFHxA, HFPO-DA, PFHxS, and 6:2 FTOH) were assessed in recombinant CYP1A2, − 2B6, −2C19, −2E1, and −3A4 enzymes. Most of the short-chain PFAS, except for PFHxS, tested did not result in significant inhibition up to 100 μM. PFOS inhibited recombinant CYP1A2, −2B6, −2C19, and −3A4 enzymes. However, concentrations where inhibition occurred, were all higher than the averages reported in population biomonitoring studies, with IC50 values higher than 10 µM. We also evaluated the activities of CYP1A2 and CYP3A4 in HepaRG monolayers following 48 h exposures of the short-chain PFAS at two concentrations (1 nM or 1 µM) and with or without an inducer (benzo[a]pyrene, BaP, for CYP1A2 and rifampicin for CYP3A4). Our findings suggest that both 1 nM and 1 µM exposures to short-chain PFAS can modulate the CYP1A2 activity induced by BaP. Except for PFHxS, the short-chain PFAS appear to have little effect on CYP3A4 activity. Understanding the effects of PFAS exposure on biotransformation can shed light on the mechanisms of PFAS toxicity and aid in developing effective strategies for managing chemical risks, enabling regulators to make more informed decisions.http://www.sciencedirect.com/science/article/pii/S2666027X23000142BiotransformationCYP450CYP1A2CYP3A4PFASIn vitro |
| spellingShingle | Megan E. Solan Ramon Lavado Effects of short-chain per- and polyfluoroalkyl substances (PFAS) on human cytochrome P450 (CYP450) enzymes and human hepatocytes: An in vitro study Current Research in Toxicology Biotransformation CYP450 CYP1A2 CYP3A4 PFAS In vitro |
| title | Effects of short-chain per- and polyfluoroalkyl substances (PFAS) on human cytochrome P450 (CYP450) enzymes and human hepatocytes: An in vitro study |
| title_full | Effects of short-chain per- and polyfluoroalkyl substances (PFAS) on human cytochrome P450 (CYP450) enzymes and human hepatocytes: An in vitro study |
| title_fullStr | Effects of short-chain per- and polyfluoroalkyl substances (PFAS) on human cytochrome P450 (CYP450) enzymes and human hepatocytes: An in vitro study |
| title_full_unstemmed | Effects of short-chain per- and polyfluoroalkyl substances (PFAS) on human cytochrome P450 (CYP450) enzymes and human hepatocytes: An in vitro study |
| title_short | Effects of short-chain per- and polyfluoroalkyl substances (PFAS) on human cytochrome P450 (CYP450) enzymes and human hepatocytes: An in vitro study |
| title_sort | effects of short chain per and polyfluoroalkyl substances pfas on human cytochrome p450 cyp450 enzymes and human hepatocytes an in vitro study |
| topic | Biotransformation CYP450 CYP1A2 CYP3A4 PFAS In vitro |
| url | http://www.sciencedirect.com/science/article/pii/S2666027X23000142 |
| work_keys_str_mv | AT meganesolan effectsofshortchainperandpolyfluoroalkylsubstancespfasonhumancytochromep450cyp450enzymesandhumanhepatocytesaninvitrostudy AT ramonlavado effectsofshortchainperandpolyfluoroalkylsubstancespfasonhumancytochromep450cyp450enzymesandhumanhepatocytesaninvitrostudy |