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Role of the ABCG2 transporter in the biodistribution of the food-borne uremic toxin p-cresyl sulfate
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  • Published: 21 February 2026

Role of the ABCG2 transporter in the biodistribution of the food-borne uremic toxin p-cresyl sulfate

  • Alicia Millán-García1,
  • Laura Álvarez-Fernández1,
  • Miriam Velasco-Díez1,
  • Diana Huertas-Álvarez1,
  • Álvaro López-García1,
  • Álvaro de la Fuente1,
  • Gracia Merino1 &
  • …
  • Esther Blanco-Paniagua1 

Scientific Reports , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Biochemistry
  • Gastroenterology
  • Microbiology

Abstract

The ATP-binding cassette transporter G2 (ABCG2) is a membrane transporter that conditions pharmacokinetics, systemic exposure, and milk secretion of drugs, natural and food-derived compounds, including gut-derived metabolites. p-Cresyl sulfate (pCS), a well-known uremic toxin, is the main metabolite of p-Cresol (pC), produced from dietary aromatic amino acids by gut microbiota. We aimed to characterize the in vitro and in vivo interaction of pCS with the ABCG2 transporter. Using MDCK–II cells overexpressing the transporter, we found that pCS is an in vitro substrate of ABCG2. Furthermore, using wild-type and Abcg2−/− mice, we showed that plasma AUC0−240 min for Abcg2−/− was almost 1.6-fold higher than for wild-type mice. Regarding tissue distribution, the liver, kidney, small intestine, testis, and spleen from Abcg2−/− mice showed significantly higher pCS levels versus the wild-type group. Moreover, pCS accumulation in small intestine content retrieved from wild-type mice was 2-fold higher than in the Abcg2−/− group. Finally, we proved that Abcg2 also affects pCS secretion into milk, with a more than 3-fold higher accumulation in milk and almost 6-fold higher milk-to-plasma ratio of wild-type versus Abcg2−/− mice. Overall, our results disclose that Abcg2 significantly affects plasma levels, biodistribution and milk secretion of pCS, thereby modulating its biological activity.

Data availability

The datasets used in this study are available in online repositories and can be found at the following link: https://open.scayle.es/dataset/millan-garcia_2026.

Abbreviations

AB:

Apical to basolateral

ABCG2:

ATP-binding cassette transporter G2

AUC:

Area under the plasma concentration-time curve

BA:

Basolateral to apical

bABCG2:

Bovine ABCG2

BCRP:

Breast cancer resistance protein

Cmax :

Maximum plasma concentration

DMEM:

Dulbecco’s modified Eagle’s medium

HEPES:

4-(2‐hydroxyethyl) − 1‐piperazineethanesulphonic acid

hABCG2:

Human ABCG2

IQ:

2-amino-3-methylimidazo[4,5-f]quinoline

LOD:

Limit of detection

LOQ:

Limit of quantification

mAbcg2:

Murine Abcg2

MDCK-II:

Madin-Darby canine kidney

oABCG2:

Ovine ABCG2

pC:

p-Cresol

pCG:

p-Cresyl glucuronide

pCS:

p-Cresyl sulfate

Phe:

Phenylalanine

PhIP:

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

SNPs:

Single-nucleotide polymorphisms

SULT1A1:

Sulfotransferase 1A1

Tyr:

Tyrosine

UPLC:

Ultra-performance liquid chromatography

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Acknowledgements

The authors thank A.H. Schinkel (The Netherlands Cancer Institute, Amsterdam, The Netherlands), who kindly provided parental MDCK–II cells and their murine Abcg2 and ABCG2–transduced subclones, as well as Abcg2 knockout mice.

Funding

The authors declare that financial support was received for the research, authorship and/or publication of this article. This work was supported by the research projects PID2021-125660OB-I00 and PID2024-161728OB-I00 (MCIN/AEI/10.13039/501100011033/FEDER “Una manera de hacer Europa”) and by predoctoral grants (FPU23/00153 grant to A.M.-G.) from the Spanish Ministry of Education, Culture and Sport.

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  1. Department of Biomedical Sciences–Physiology, Faculty of Veterinary Medicine, Animal Health Institute (INDEGSAL), Universidad de León, Campus de Vegazana, León, 24071, Spain

    Alicia Millán-García, Laura Álvarez-Fernández, Miriam Velasco-Díez, Diana Huertas-Álvarez, Álvaro López-García, Álvaro de la Fuente, Gracia Merino & Esther Blanco-Paniagua

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  1. Alicia Millán-García
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Contributions

Conceptualization, A.M.-G., E.B.-P. and G.M.; methodology, A.M.-G., L.Á.-F., M.V-C, D.H-Á, Á.L-G, Á.F. and E.B.-P.; investigation and formal analysis, A.M.-G., L.Á.-F, M.V-C, D.H-Á, and Á.L-G; data curation and writing-original draft preparation, A.M.-G.; writing-review and editing, L.Á.-F., E.B.-P. and G.M.; validation, resources and project administration, G.M. and Á.F.; supervision and funding acquisition, G.M. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Esther Blanco-Paniagua.

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Millán-García, A., Álvarez-Fernández, L., Velasco-Díez, M. et al. Role of the ABCG2 transporter in the biodistribution of the food-borne uremic toxin p-cresyl sulfate. Sci Rep (2026). https://doi.org/10.1038/s41598-026-39854-0

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  • Received: 16 December 2025

  • Accepted: 09 February 2026

  • Published: 21 February 2026

  • DOI: https://doi.org/10.1038/s41598-026-39854-0

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Keywords

  • p-Cresyl sulfate
  • ABCG2
  • Milk secretion
  • Plasma levels
  • Tissue distribution
  • Transepithelial transport assays
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