Abstract
Organic anion transporters (OATs) facilitate the renal secretion of weak organic acids including endogenous metabolites and drugs. Besides acidic metabolites of neurotransmitters, neuroactive tryptophan metabolites like kynurenate (KYNA), 3- hydroxykynurenine (3-HK) and quinolinate (QUIN) are postulated to be excreted via a probenecid-sensitive transport System. Immunohistochemical analyses in mouse kidneys revealed the localization of mouse OATl (mOAT1) in proximal convoluted tubules. Examinations of mouse brain sections showed positive stainings of cortical neurons. Additionally, we investigated the interaction of mOATl with several tryptophan metabolites. We transiently transfected COS 7 cells with mOAT1 and measured the influence of tryptophan metabolites on [~HIPAH u take 1mM of probenecid, KYNA, 3-HK, 5- hydroxyindoEte (i-HIAA) and anthranilate (ANTRA) decreased PAH uptake by 50-85%, demonstrating that all these compounds bind to OAT1. 1mM QUIN showed only a slight, but significant inhibition of PAH uptake. Preloading the cells with 1mM glutarate, KYNA, 3-HK, 5-HIAA, ANTRA or QUIN revealed a substantial trans-stimulation of PAH uptake by glutarate, and a significant effect for 5-HIAA, indicating that this compound is translocated by OAT1.
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