Toxicity of N-(3,5-dichlorophenyl)succinimide and metabolites to rat renal proximal tubules and mitochondria.
The acute nephrotoxicity caused by N-(3,5-dichlorophenyl) succinimide (NDPS) has been shown to be due to a metabolite(s) of the parent compound. This study examined the toxicity of NDPS, its known metabolites N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS), N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (NDHSA), N-(3,5-dichlorophenyl)malonamic acid (DMA), N-(3,5-dichlorophenyl)succinamic acid (NDPSA), and two postulated metabolites N-(3,5-dichlorophenyl)maleamic acid (NDPMA) and N-(3,5-dichlorophenyl)maleimide (NDPM) to suspensions of renal proximal tubules (RPT) prepared from male Fischer 344 rats. Tubule viability and mitochondrial function were not adversely affected by exposure of RPT to either 1 mM NDPS, NDHS, NDHSA, DMA, NDPSA, or NDPMA for 4 h. However, NDPM caused a concentration-(25-100 microM) and time-dependent (0.25-4 h) loss in basal and nystatin stimulated oxygen consumption and tubule viability. Investigations using isolated renal cortical mitochondria (RCM) showed that NDPM was a potent inhibitor of mitochondrial function. Isolated RCM respiring on pyruvate/malate and exposed to NDPM exhibited a concentration (25-100 microM) dependent decrease in state 3 and state 4 respiration. Inhibition of mitochondrial state 3 respiration by NDPM was mediated through site 1 of the respiratory chain. NDPM did not inhibit cytochrome c-cytochrome oxidase or the electron transport chain. These results indicated that NDPS, its known metabolites, and NDPMA were not directly toxic to rat RPT. However, the postulated metabolite NDPM, was a potent tubule cytotoxicant that inhibited mitochondrial function in isolated RCM and RPT and may produce cell death through this mechanism.
Aleo
M D
MD
Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens 30602.
Rankin
G O
GO
Cross
T J
TJ
Schnellmann
R G
RG
D000818:Animals; D007672:Kidney Cortex / Q000187:drug effects / Q000648:ultrastructure; D007687:Kidney Tubules, Proximal / Q000187:drug effects*; D008297:Male; D008298:Maleates / Q000633:toxicity; D008301:Maleimides / Q000633:toxicity; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D013388:Succinimides / Q000378:metabolism / Q000633:toxicity*
D008298:Maleates; D008301:Maleimides; D013388:Succinimides; C068137:N-(3,5-dichlorophenyl)maleimide; C007352:N-(3,5-dichlorophenyl)succinimide; C068136:N-(3,5-dichlorophenyl)maleamic acid