Mercapturic acids (N-acetylcysteine S-conjugates) as endogenous substrates for the renal organic anion transporter-1

J M Pombrio, A Giangreco, L Li, M F Wempe, M W Anders, D H Sweet, J B Pritchard, N Ballatori

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49 Citations (Scopus)

Abstract

Mercapturic acids are N-acetyl-L-cysteine S-conjugates that are formed from a range of endogenous and exogenous chemicals. Although the kidney is a major site for elimination of mercapturic acids, the transport mechanisms involved have not been identified. The present study examined whether mercapturic acids are substrates for the renal basolateral organic anion transporter-1 (Oat1) from rat kidney. This carrier mediates uptake of organic anions from the bloodstream in exchange for intracellular alpha-ketoglutarate. Uptake of [(3)H]p-aminohippuric acid (PAH) in Oat1-expressing Xenopus laevis oocytes was strongly inhibited by S-(2,4-dinitrophenyl)-N-acetyl-L-cysteine (DNP-NAC) and by all other mercapturic acids tested, including the endogenous mercapturic acid N-acetyl-leukotriene E(4). Inhibition by the mercapturic acids was competitive, which is consistent with the hypothesis that these compounds are substrates for Oat1. This conclusion was supported by the direct demonstration of saturable [(35)S]DNP-NAC uptake in Oat1-expressing oocytes. [(35)S]DNP-NAC uptake was inhibited by PAH and other mercapturic acids and was stimulated in oocytes preloaded with glutarate. The apparent K(m) value for DNP-NAC uptake was only 2 microM, indicating that this mercapturic acid is a high affinity substrate for Oat1. Together, these data indicate that clearance of endogenous mercapturic acids is an important function of the renal organic anion transporter.

Original languageEnglish
Pages (from-to)1091-9
Number of pages9
JournalMolecular Pharmacology
Volume60
Issue number5
DOIs
Publication statusPrint publication - Nov 2001
Externally publishedYes

Keywords

  • Acetylcysteine/analogs & derivatives
  • Animals
  • Humans
  • Kidney/metabolism
  • Oocytes/metabolism
  • Organic Anion Transport Protein 1/metabolism
  • Tritium
  • Xenopus laevis
  • p-Aminohippuric Acid/metabolism

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