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Folate Transport Pathways Regulate Urinary Excretion of 5-Methyltetrahydrofolate in Isolated Perfused Rat Kidney^1,2,3,

Department of Pharmacology and Therapeutics, Louisiana State University Medical Center, Shreveport, LA 71130-3932

The reabsorption of 5-methyltetrahydrofolic acid (5-CH₃-H₄PteGlu) by the renal proximal tubule has an important role in the maintenance of plasma folate concentrations. However, the mechanism by which this vitamin traverses the renal epithelium remains to be determined. Studies in cultured cells have suggested that the folate receptor in association with a probenecid-sensitive anion carrier may be involved in the transmembrane transport of the vitamin. Because 5-CH₃-H₄PteGlu is reabsorbed and metabolized in the isolated perfused rat kidney (IPRK) in a similar manner to in vivo models, the IPRK was used to evaluate pathways involved in folate reabsorption. Reabsorption of 5-CH₃-H₄PteGlu could not be saturated in the isolated perfused rat kidney, even at concentrations up to 2 µmol/L. Folic acid (PteGlu) was used as a competitive inhibitor of FR-dependent reabsorption of 5-CH₃-H₄PteGlu. When 5-CH₃-H₄PteGlu was maintained at 1 nmol/L (a concentration at which receptor-mediated transport should be maximal), PteGlu (up to 100 nmol/L) had no effect on reabsorption. The addition of probenecid (1 mmol/L) did not affect the reabsorption of 5-CH₃-H₄PteGlu but inhibited the fractional excretion of the anion para-aminohippurate. Probenecid also inhibited the urinary excretion of 5-CH₃-H₄PteGlu metabolites, indicating that reabsorbed 5-CH₃-H₄PteGlu was metabolized to products that were subsequently secreted into the urine by anion exchange pathways. The physiological importance of a folate receptor-mediated reabsorption of 5-CH₃-H₄PteGlu appears to be minor in the isolated perfused rat kidney, whereas nonspecific pathways appear to play a major role in the renal folate reabsorption.

KEY WORDS: • probenecid • renal folate reabsorption • membrane folate transport • rats

¹ Presented in part at Experimental Biology 93, March 28–April 1, 1993, New Orleans, LA [Muldoon, R.T. & McMartin, K.E. (1993) The effect of folic acid on 5-methyltetrahydrofolic acid reabsorption in the isolated perfused rat kidney. FASEB J. 7:A727 (abs.)].

² Supported by National Institutes of Health grant RO1-AA05308.

³ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

⁴ To whom correspondence should be addressed.

Manuscript received 10 April 1995. Revision accepted 8 September 1995.