Acute effects of a γ-glutamylated derivative of S-(1,2-dichlorovinyl)-l-cysteine on renal function and ultrastructure in pentobarbital-anesthetized dogs: Site-specific toxicity involving S1 and S2 cells of the proximal tubule

Richard E. Ridgewell From the Department of Pharmacology, Medical College of Ohio, PO Box 10008, Toledo, OH 43699-0008.

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Mark E. Krejci From the Department of Pharmacology, Medical College of Ohio, PO Box 10008, Toledo, OH 43699-0008.

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Daniel A. Koechel From the Department of Pharmacology, Medical College of Ohio, PO Box 10008, Toledo, OH 43699-0008.

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Summary

It has been established that l-γ-glutamylated derivatives of α-amino acids are delivered more efficiently to the kidneys than are the parent α-amino acids. Therefore, we synthesized L-γ-glutamyl-S-(1,2-dichlorovinyl)-l-cysteine (L-γ-glutamyl-l-dcvc), the simplest l-γ-glutamylated derivative of the nephrotoxic α-amino acid S-(1,2-dichlorovinyl)-l-cysteine (l-dcvc), and investigated its effects on renal function and ultrastructure in pentobarbital-anesthetized dogs. Intravenous doses of 23.15 and 92.60 (μmol of L-γ-glutamyl-l-dcvc/kg of body weight induced significant increases in urinary protein output and significant decreases in the clearance of inulin during the 6-hour post-injection period. Changes were not observed in any of the other 13 renal function variables or in the 11 plasma and blood variables that were monitored throughout the same period. Both doses of L-γ-glutamyl-l-dcvc induced renal ultrastructural lesions in the S1 and S2 cells of the canine proximal tubule; the remaining 8 cell types downstream and the glomeruli were not damaged. The onset and magnitude of renal function changes and the cell types affected by L-γ-glutamyl-l-dcvc were virtually identical to those observed previously following iv administration of equivalent doses of l-dcvc to pentobarbital-anesthetized dogs. Rapid removal of the l-γ-glutamyl group from L-γ-glutamyl-l-dcvc (ie, deglutamylation) resulting in formation of the parent α-amino acid, l-dcvc, can best explain the extreme similarity in the nephrotoxic profiles of these 2 toxicants.

Summary

It has been established that l-γ-glutamylated derivatives of α-amino acids are delivered more efficiently to the kidneys than are the parent α-amino acids. Therefore, we synthesized L-γ-glutamyl-S-(1,2-dichlorovinyl)-l-cysteine (L-γ-glutamyl-l-dcvc), the simplest l-γ-glutamylated derivative of the nephrotoxic α-amino acid S-(1,2-dichlorovinyl)-l-cysteine (l-dcvc), and investigated its effects on renal function and ultrastructure in pentobarbital-anesthetized dogs. Intravenous doses of 23.15 and 92.60 (μmol of L-γ-glutamyl-l-dcvc/kg of body weight induced significant increases in urinary protein output and significant decreases in the clearance of inulin during the 6-hour post-injection period. Changes were not observed in any of the other 13 renal function variables or in the 11 plasma and blood variables that were monitored throughout the same period. Both doses of L-γ-glutamyl-l-dcvc induced renal ultrastructural lesions in the S1 and S2 cells of the canine proximal tubule; the remaining 8 cell types downstream and the glomeruli were not damaged. The onset and magnitude of renal function changes and the cell types affected by L-γ-glutamyl-l-dcvc were virtually identical to those observed previously following iv administration of equivalent doses of l-dcvc to pentobarbital-anesthetized dogs. Rapid removal of the l-γ-glutamyl group from L-γ-glutamyl-l-dcvc (ie, deglutamylation) resulting in formation of the parent α-amino acid, l-dcvc, can best explain the extreme similarity in the nephrotoxic profiles of these 2 toxicants.

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