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Renal Reabsorption of Folates: Pharmacological and Toxicological Snapshots

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, 8006 Zurich, Switzerland
Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, 4056 Basel, Switzerland
Author to whom correspondence should be addressed.
Nutrients 2019, 11(10), 2353;
Received: 14 August 2019 / Revised: 24 September 2019 / Accepted: 26 September 2019 / Published: 2 October 2019
(This article belongs to the Special Issue Dietary Folate and Human Health)
Folates are water-soluble B9 vitamins that serve as one-carbon donors in the de novo synthesis of thymidylate and purines, and in the conversion of homocysteine to methionine. Due to their key roles in nucleic acid synthesis and in DNA methylation, inhibiting the folate pathway is still one of the most efficient approaches for the treatment of several tumors. Methotrexate and pemetrexed are the most prescribed antifolates and are mainly used in the treatment of acute myeloid leukemia, osteosarcoma, and lung cancers. Normal levels of folates in the blood are maintained not only by proper dietary intake and intestinal absorption, but also by an efficient renal reabsorption that seems to be primarily mediated by the glycosylphosphatidylinositol- (GPI) anchored protein folate receptor α (FRα), which is highly expressed at the brush-border membrane of proximal tubule cells. Folate deficiency due to malnutrition, impaired intestinal absorption or increased urinary elimination is associated with severe hematological and neurological deficits. This review describes the role of the kidneys in folate homeostasis, the molecular basis of folate handling by the kidneys, and the use of high dose folic acid as a model of acute kidney injury. Finally, we provide an overview on the development of folate-based compounds and their possible therapeutic potential and toxicological ramifications. View Full-Text
Keywords: acute kidney injury; folate; folate receptor; folic acid; nephrotoxicity; renal reabsorption acute kidney injury; folate; folate receptor; folic acid; nephrotoxicity; renal reabsorption
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Samodelov, S.L.; Gai, Z.; Kullak-Ublick, G.A.; Visentin, M. Renal Reabsorption of Folates: Pharmacological and Toxicological Snapshots. Nutrients 2019, 11, 2353.

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