Renal Reabsorption of Folates: Pharmacological and Toxicological Snapshots.

Sophia L Samodelov,Zhibo Gai,Michele Visentin,Gerd A Kullak-Ublick

doi:10.3390/nu11102353

Abstract

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.

Highlights

Folates are water-soluble B9 vitamins that consist of a pteridine moiety, a para-aminobenzoate group and a tail of glutamate residues, which is important for the intracellular retention of folates.The redox state of pteridine defines oxidized and reduced folates, with the latter being the naturally occurring folates
Renal reabsorption is important for folate homeostasis and is mainly mediated by folate receptor α (FRα)
Under folate deficiency, other endocytic or transporter-mediated processes come into play for the recycling of folates

Summary

Introduction

Folates are water-soluble B9 vitamins that consist of a pteridine moiety, a para-aminobenzoate group and a tail of glutamate residues, which is important for the intracellular retention of folates. Folates serve as one-carbon donors and provide a methylene group for the de novo synthesis of thymidylate from deoxyuridylate and two formate groups for the de novo synthesis of the purines. The oxidized form, does not occur naturally and, as it is not the physiological form, it is practically absent in the plasma, with the exception of the populations of those countries that have embraced folic acid food fortification strategies, such as those in North America In these populations, folic acid accounts for about 5% of the total circulating folate pool [7]. Normal levels of folates in the blood are maintained by proper dietary intake and intestinal absorption, and by an efficient renal reabsorption mainly mediated by the glycosylphosphatidylinositol- (GPI) anchored protein folate receptor α (FRα) [20]. We provide an overview of folate-conjugated drugs viewed from the kidney standpoint

Mechanisms of Folate Tubular Reabsorption

Folic Acid-Induced Acute Kidney Injury Model

Nephrotoxicity of Folate-Conjugated Chemotherapy and Radiotherapy

Folic Acid-Bound Drugs for the Treatment of Polycystic Kidney

Findings

Conclusions