Details

Autor(en) / Beteiligte

• Koechel, Daniel A.
• Krejci, Mark E.
• Ridgewell, Richard E.

Titel

S-(1,2-dichlorovinyl)-3-mercaptopropionic acid effects of renal function and ultrastructure in pentobarbital-anesthetized dogs: site-specific toxicity and evidence for its toxification via the pathway responsible for β-oxidation of fatty acids

Ist Teil von

• Toxicology (Amsterdam), 1993-12, Vol.85 (1), p.1-24

Ort / Verlag

Shannon: Elsevier Ireland Ltd

Erscheinungsjahr

1993

Link zum Volltext

Quelle

Elsevier Journal Backfiles on ScienceDirect (DFG Nationallizenzen)

Beschreibungen/Notizen

• S-(1,2-dichlorovinyl)-3-mercaptopropionic acid (DCV-3-MPA) was equally nephrotoxic to spontaneously-respiring and mechanically-ventilated, pentobarbital-anesthetized dogs. Its nephrotoxicity was expressed as dose-dependent changes in key renal function parameters, in proximal tubular S 1, S 2 and S 3 cellular architecture and in the ability of the kidneys to respond maximally to ethacrynic acid, an efficacious loop diuretic. The nephrotoxicity associated with DCV-3-MPA was not the result of extrarenal actions such as hypoxemia and subsequent renal tissue hypoxia because mechanical ventilation was not protective. Four lines of evidence suggested that DCV-3-MPA was taken-up by renal proximal tubular cells like a fatty acid and metabolized by the mitochondrial β-oxidation pathway to a reactive nephrotoxic intermediate: (i) probenecid pretreatment, which reduces the renal uptake of many organic anions but fails to do so with anions of fatty acids, failed to modify the nephrotoxicity of DCV-3-MPA; (ii) the next higher and lower homologues of DCV-3-MPA (i.e., S-(1,2-dichlorovinyl)-4-mercaptobutanoic acid (DCV-4-MBA) and S-(1,2-dichlorovinyl)-mercaptoacetic acid (DCV-MAA)) cannot yield the same reactive intermediate as DCV-3-MPA upon β-oxidation and neither was nephrotoxic; (iii) DCV-MAA was found in plasma and urine following administration of DCV-4-MBA and (iv) the renal mitochondria were reproducibly damaged by DCV-3-MPA whereas the peroxisomes, which are also capable of performing β-oxidation of certain fatty acids, were unscathed.