Organic anion transport
Xenobiotic trans formation
Structure activity relationship
Springer Online Journal Archives 1860-2000
Abstract In order to evaluate the specificity of the renal contraluminal PAH transport system for amino acids, oligopeptides and their conjugates, the inhibitory potency of these substances against contraluminal [3H] PAH influx has been determined. For this, inhibition of 3H-PAH flux from the interstitium into cortical tubular cells of the rat kidney in situ has been measured. Apparent Ki values were evaluated by a computer program assuming competitive inhibition. Unconjugated amino acids (glycine, cysteine, alanine, leucine, phenylalanine, tyrosine, aspartate, glutamate, arginine, ornithine and lysine) do not inhibit [3H] PAH influx. The very hydrophobic tryptophan, however, does. N-α-methylation does not change this behaviour. N-α-acetylation does not evoke interaction with the PAH transporter when it occurs with glycine, cysteine (to yield mercapturic acid), arginine, ornithine and lysine. However, it renders alanine, leucine, phenylalanine, tryptophan, L-aspartate moderately, and L-glutamate strongly, inhibitory. The acetylated D-isomers of alanine, leucine and phenylalanine exert a higher inhibitory potency compared with the respective L-isomers. N-α-benzoylation of L-lysine is ineffective. N-α-benzoylation, however, evokes interaction with the PAH transporter, when it occurs with ornithine 〈 arginine 〈 histidine 〈 glycine = leucine 〈 alanine = phenylalanine = aspartate = glutamate. Dipeptides interact with the PAH transporter according to their hydrophobicity (Nozaki scale down to 0.9, Fauchère scale up to 1.0). N-acetylation does not change this behaviour. Hydrophobicity also renders oligopeptides, as angiotensin II, inhibitory against PAH transport. Similarly the anionic angiotensin I converting enzyme inhibitors Captopril, Enalapril and Ramipril inhibit contraluminal PAH influx. The same holds for the Amanita phalloides peptides α- and β-amanitin, phalloin, phallacidin and Tyr5-carboxymethyl antamanide. Conjugation with L-glutathione renders only strongly hydrophobic xenobiotics inhibitory against PAH transport: S-(4-azidophenacyl)-= S-(4-chlorophenacyl)-〈 S-(1,2,2-trichlorovinyl)-〈 S-(1,2,3,4,4-pentachlorobuta-dienyl)- 〈 S-(n-decyl)-. Processing to the L-cysteine conjugate augments the inhibitory potency and additional N-acetylation of the α-amino group augments it even more. Thus, the above mentioned conjugation, which creates hydrophobic molecules with a negative ionic charge, renders it reactive with the PAH transporter. If a remaining positive change at the α-NH 3 + is eliminated by N-acetylation the affinity is further augmented.
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