Lack of Interaction of the Fluorosurfactant C6O4 with Human Renal Transporters: In Vitro/in Silico Analysis
Open accessAbstract
C6O4 is a water soluble perfluoroether carboxylic acid ammonium salt used as surfactant in the synthesis of fluoropolymers. Available experimental data in rats exposed by the oral route indicate it is eliminated in urine. Previous studies with various linear perfluorocarboxylic acids have suggested that these compounds are substrates of renal membrane transporters in rats and humans, and that the interaction with basal and apical membrane transporters can influence the elimination kinetic by these organisms and explain, in part, the observed differences in the respective half-lives. In particular, apical transporters may contribute to the reuptake of these exogenous compounds from the tubule lumen. The present study was designed to investigate the uptake of C6O4 in two renal cell lines transiently transfected with the human apical membrane transporters, organic anion transporter 4 (OAT4), and urate transporter 1 (URAT1). The uptake of the linear perfluorohexanoic acid (PFC6) was evaluated in parallel. While the uptake of the conjugated steroid estrone-3-sulfate (E3S), a known substrate for renal transporters, and of PFC6 was clearly observed in both cell types transfected with either OAT4 or URAT1, no significant uptake of C6O4 was measured under the same test conditions. The results of the transporter's functionality measured in vitro were consistent with molecular docking simulations. Both outward and inward models of the transporters showed a reduced interaction between C6O4 and URAT1 or OAT4. In contrast, more stable interactions were predicted for PFC6 and PFOA, as well as for the E3S substrate, as shown by the respective docking scores reflecting the binding strength and by the poses assumed in the transporter channels. Altogether, the in vitro and in silico modeling results showed a low reuptake potential and limited interactions of C6O4 molecule with two human apical membrane transporters, contrasting with the more efficient reuptake of PFC6 from the tubule lumen. These results suggest reabsorption from the proximal tubule by apical renal transporters is not likely to interfere with the elimination pathway of C6O4 in humans.
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C6O4 showed negligible uptake in two renal cell lines transfected with either URAT1 or OAT4, whereas both URAT1- and OAT4-transfected cells displayed uptake of the reference PFAS PFC6.
“By contrast, an examination of a new-generation PFAS, C6O4, in two renal cell lines transfected with either URAT1 or OAT4 showed negligible C6O4 uptake under the experimental conditions, whereas both URAT1- and OAT4-transfected cells displayed uptake of the reference PFAS, perfluorohexanoic acid (PFC6).”
From The EU’s Per- and Polyfluoroalkyl Substances (PFAS) Ban: A Case of Policy over Science (2023) · cites this paper as [45]
Different transport mechanisms exist for different PFAS, with these mechanisms potentially influencing their elimination and bioaccumulation in the body.
“These results highlight the existence of different transport mechanisms for different PFAS, with these mechanisms potentially influencing their elimination and bioaccumulation in the body [45].”
From The EU’s Per- and Polyfluoroalkyl Substances (PFAS) Ban: A Case of Policy over Science (2023) · cites this paper as [45]
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- Authors
- Bruno, S., Bersani, M., Astore, S., Chiabotto, G., Barge, A., Binello, A., & Spyrakis, F.
- Affiliations
- University of Turin (IT)
- Corresponding author
- Bruno, Stefania
- ORCID
- Venue
- Toxicology
- Publisher
- Elsevier BV
- Published
- 2022-06
- Volume
- 476
- Pages
- 153257
- ISSN
- 0300-483X (ISSN-L)
- OpenAlex
- W4285035084
- Cited by
- 7
- References
- 39
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 1
- FWCI
- 0.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Toxicology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PORTO@Iris (submittedVersion, cc-by-nc-nd)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Topics
- Physical Sciences › Environmental Science › Environmental Chemistry › Per- and polyfluoroalkyl substances research
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- fluorosurfactants, renal transporters, URAT1, perfluorocarboxylic acids, perfluorooctanoic acid, estrone-3-sulfate, tubular reabsorption, molecular docking, urinary excretion
- MeSH terms
- Animals, Biological Transport, Humans, Kidney, Membrane Transport Proteins, Organic Anion Transporters, Rats, Molecular Docking Simulation
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