RT Journal Article
SR Electronic
T1 Mercapturic Acids (<em>N</em>-Acetylcysteine<em>S</em>-Conjugates) as Endogenous Substrates for the Renal Organic Anion Transporter-1
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1091
OP 1099
DO 10.1124/mol.60.5.1091
VO 60
IS 5
A1 Pombrio, James M.
A1 Giangreco, Adam
A1 Li, Liqiong
A1 Wempe, Michael F.
A1 Anders, M. W.
A1 Sweet, Douglas H.
A1 Pritchard, John B.
A1 Ballatori, Nazzareno
YR 2001
UL http://molpharm.aspetjournals.org/content/60/5/1091.abstract
AB Mercapturic acids are N-acetyl-l-cysteineS-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 α-ketoglutarate. Uptake of [3H]p-aminohippuric acid (PAH) in Oat1-expressing Xenopus laevis oocytes was strongly inhibited byS-(2,4-dinitrophenyl)-N-acetyl-l-cysteine (DNP-NAC) and by all other mercapturic acids tested, including the endogenous mercapturic acid N-acetyl-leukotriene E4. 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 [35S]DNP-NAC uptake in Oat1-expressing oocytes. [35S]DNP-NAC uptake was inhibited by PAH and other mercapturic acids and was stimulated in oocytes preloaded with glutarate. The apparentK m value for DNP-NAC uptake was only 2 μM, 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.