4-Maleimidohippuric acid--a tailor-made, direct, site-specific nephrotoxin: effects on renal function and ultrastructure in pentobarbital-anesthetized dogs.
A model has been proposed to explain at least one of the possible pathways through which a xenobiotic might produce proximal tubule necrosis. The model is formulated on the idea that a compound must possess two structural features: (i) a carboxyl or amino acid moiety that would allow for selective uptake into proximal tubule cells via the strategically located antiluminal membrane-bound organic anion transport system or the luminal membrane-bound amino acid transport system(s), respectively, and (ii) a highly reactive moiety that can directly alkylate proximal tubular components, or a moiety that can be biotransformed within proximal tubular cells to such a substance. In an attempt to validate the proposed structural features as prerequisites for xenobiotic induction of proximal tubular necrosis, a novel compound, 4-maleimidohippuric acid (4-MHA), was synthesized which possesses an anionic group and a reactive moiety. Following the administration of 4-MHA directly into the renal artery of pentobarbital-anesthetized dogs, specific unilateral ultrastructural damage was noted only in the S1 and S2 cell types of the proximal tubule; the most notable renal function changes included proteinuria and glucosuria. Anionic, but non-alkylating, relatives of 4-MHA failed to alter renal function or ultrastructure. The specific proximal tubular toxicity of 4-MHA validates the proposed structural requirements for induction of proximal tubular necrosis.
Koechel
D A
DA
Department of Pharmacology, Medical College of Ohio, Toledo 43699-0008.
Krejci
M E
ME
Bretz
N S
NS
D000704:Analysis of Variance; D000758:Anesthesia; D000818:Animals; D004285:Dogs; D004976:Ethacrynic Acid / Q000494:pharmacology; D005260:Female; D006626:Hippurates / Q000633:toxicity*; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced* / Q000652:urine; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D008297:Male; D008301:Maleimides / Q000633:toxicity*; D010424:Pentobarbital
D006626:Hippurates; D008301:Maleimides; C092417:4-(2,3-dimethylmaleimido)hippuric acid; C092416:4-maleimidohippuric acid; D010424:Pentobarbital; D004976:Ethacrynic Acid