Deuterium isotope effect in acute N-(3,5-dichlorophenyl)succinimide-induced nephrotoxicity.
Deuterium labelling of the succinimide ring of N-(3,5-dichlorophenyl) succinimide (NDPS) markedly reduced the acute nephrotoxicity produced by NDPS administration to Fischer 344 rats. Administration of the deuterium-labelled derivative, NDPS-d4, to male Fischer 344 rats failed to produce the marked diuresis, increased proteinuria, glucosuria, hematuria, elevated blood urea nitrogen (BUN) concentration and kidney weight, decreased basal p-aminohippurate (PAH) accumulation, and proximal tubular necrosis which are characteristic of NDPS-induced nephrotoxicity. However, lactate-stimulated PAH and tetraethylammonium (TEA) accumulation were decreased by NDPS-d4 (1.0 mmol/kg). The lack of nephrotoxicity produced by NDPS-d4 suggests that oxidation at the carbon-carbon bridge of the succinimide ring is an important biotransformation step in the generation of the nephrotoxic species of NDPS.
D000818:Animals; D001711:Biotransformation; D003903:Deuterium / Q000494:pharmacology*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000378:metabolism / Q000633:toxicity*
D013388:Succinimides; C007352:N-(3,5-dichlorophenyl)succinimide; D003903:Deuterium