S-(1,2-dichlorovinyl)-3-mercaptopropionic acid effects on renal function and ultrastructure in pentobarbital-anesthetized dogs: site-specific toxicity and evidence for its toxification via the pathway responsible for beta-oxidation of fatty acids.
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 S1, S2 and S3 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 beta-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 beta-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 beta-oxidation of certain fatty acids, were unscathed.
Koechel
D A
DA
Department of Pharmacology, Medical College of Ohio, Toledo 43699-0008.
Krejci
M E
ME
Ridgewell
R E
RE
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D007677:Kidney Function Tests; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000648:ultrastructure*; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D008956:Models, Chemical; D009336:Necrosis; D010084:Oxidation-Reduction; D010424:Pentobarbital; D011422:Propionates / Q000378:metabolism / Q000633:toxicity*
D005227:Fatty Acids; D011422:Propionates; C007354:S-(1,2-dichlorovinyl)-3-mercaptopropionic acid; D010424:Pentobarbital