4-Maleimidohippuric acid--a tailor-made, direct, site-specific nephrotoxin: effects on renal function and ultrastructure in pentobarbital-anesthetized dogs.

Abstract

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.

• Authors: D A Koechel, M E Krejci, N S Bretz
• Journal: Toxicology (Toxicology) Vol. 96 Issue 2 Pg. 115-26 (Feb 06 1995) ISSN: 0300-483X [Print] Ireland
• PMID: 7886682 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Hippurates
• Maleimides
• 4-(2,3-dimethylmaleimido)hippuric acid
• 4-maleimidohippuric acid
• Pentobarbital
• Ethacrynic Acid

Topics

• Analysis of Variance
• Anesthesia
• Animals
• Dogs
• Ethacrynic Acid (pharmacology)
• Female
• Hippurates (toxicity)
• Kidney Diseases (blood, chemically induced, urine)
• Kidney Tubules, Proximal (drug effects, physiology, ultrastructure)
• Male
• Maleimides (toxicity)
• Pentobarbital