Nephrotoxicity of para-substituted thiobenzamide derivatives in the rat.
Histological examination, plasma urea nitrogen levels (BUN), and renal cortical slice uptake of paminohippurate (PAH) or tetraethylammonium (TEA) were used to assess the nephrotoxicity of thiobenzamide and its para-substituted derivatives in Sprague-Dawley rats. Intraperitoneal injection of p-methylthiobenzamide (PMTB) to rats resulted in dose-dependent nephrotoxicity as judged by increased BUN levels, decreased TEA uptake and histologic examination of the kidney. Para-methoxythiobenzamide and PMTB were more potent nephrotoxins than thiobenzamide, which was itself minimally nephrotoxic. Para-methylthiobenzamide-S-oxide (PMTBSO) was more nephrotoxic than PMTB. Rats were pretreated with 1-methyl-1-phenylbenzoylthiourea (MPBTU), a non-toxic arylthiourea which inhibits the metabolism and toxicity of thiocarbonyl compounds. The nephrotoxicity and hepatotoxicity of PMTB was reduced by treatment with MPBTU 30 min prior to PMTB. Pretreatment with MPBTU protected against the renal toxicity of PMTBSO. The results indicate that electron donating para-substituted thiobenzamides produce dose-dependent renal injury, dependent upon oxidative biotransformation.
Traiger
G J
GJ
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence 66045-2500.
Gammal
L M
LM
Cox
D N
DN
Haschek
W M
WM
D000577:Amides / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D001806:Blood Urea Nitrogen; D004305:Dose-Response Relationship, Drug; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000378:metabolism; D013854:Thioamides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D013890:Thiourea / Q000494:pharmacology / Q000031:analogs & derivatives; D010130:p-Aminohippuric Acid / Q000378:metabolism
D000577:Amides; D013757:Tetraethylammonium Compounds; D013854:Thioamides; C046800:1-methyl-1-phenyl-3-benzoylthiourea; D019789:Tetraethylammonium; C015539:thiobenzamide; D013890:Thiourea; D010130:p-Aminohippuric Acid