Potential metabolism and cytotoxicity of N-(3,5-dichlorophenyl)succinimide and its hepatic metabolites in isolated rat renal cortical tubule cells.
N-(3,5-Dichlorophenyl)succinimide (NDPS) is an agricultural fungicide and antimicrobial agent that produces nephrotoxicity in rats. The contribution of the kidney, if any, to the mechanism of toxicity of NDPS is not known. Therefore, the ability of isolated renal cortical tubule cells to metabolize NDPS and some of its known hepatic metabolites was studied. The cytotoxic potential of these compounds was also assessed. Renal cortical tubule cells were isolated by collagenase digestion and were incubated with the test compounds (2 mM) for 3 h. Metabolite formation was monitored by reversed phase HPLC and cell viability was assessed using trypan blue exclusion. The isolated kidney cells do not appear to metabolize NDPS or any of its known hepatic metabolites. In addition, none of these compounds were directly cytotoxic to the renal cells. However, the cells were susceptible to mercuric chloride (1 mM) and chloroform (125 or 200 mM). Intracellular glutathione levels were unaltered by the presence of NDPS in the incubations. These results suggest that NDPS and its metabolites are not directly toxic to the kidney and are not converted into the ultimate nephrotoxic species by the kidney. Extrarenal metabolism may, therefore, be critical to the expression of NDPS-induced nephrotoxicity.
Henesey
C M
CM
Department of Pharmacology and Toxicology, Philadelphia College of Pharmacy and Science, PA 19104, USA.
Harvison
P J
PJ
D000704:Analysis of Variance; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002725:Chloroform / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D005659:Fungicides, Industrial / Q000378:metabolism / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D007672:Kidney Cortex / Q000166:cytology / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008627:Mercuric Chloride / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D013388:Succinimides / Q000378:metabolism / Q000633:toxicity*; D014343:Trypan Blue / Q000737:chemistry
D005659:Fungicides, Industrial; D013388:Succinimides; C007352:N-(3,5-dichlorophenyl)succinimide; D008627:Mercuric Chloride; D002725:Chloroform; D005978:Glutathione; D014343:Trypan Blue