Nephrotoxicity of thiabendazole in mice depleted of glutathione by treatment with DL-buthionine sulphoximine.
Thiabendazole [2-(4'-thiazolyl)benzimidazole; TBZ] is widely used as an anthelmintic and a fungicide. TBZ (50-400 mg/kg body weight administered by oral intubation) produced nephrotoxicity in male ICR mice pretreated with an inhibitor of glutathione synthesis, DL-buthionine sulphoximine (BSO; 4 mmol/kg body weight, ip). The toxicity was characterized by increases in kidney: body weight ratio and serum urea nitrogen concentration and by tubular necrosis. The nephrotoxic effects were both dose and time dependent. TBZ in combination with BSO also produced decreases in p-aminohippurate accumulation and acetylation by renal cortical slices. TBZ (up to 1200 mg/kg/body weight) alone resulted in no nephrotoxicity. Administration (ip) of glutathione monomethyl ester, which is readily hydrolysed to glutathione after being transported into cells, completely protected against the toxicity caused by TBZ in combination with BSO; this result suggests that glutathione depletion is a major factor underlying the toxicological interaction between TBZ and BSO. Treatment with three inhibitors of renal microsomal cytochrome P-450-dependent monooxygenases, piperonyl butoxide, methoxsalen and carbon disulphide, all equally prevented the nephrotoxicity of TBZ given in combination with BSO. These results suggest that metabolism of TBZ is a necessary step in TBZ-induced nephrotoxicity in glutathione-depleted mice.
Mizutani
T
T
Department of Food Science and Nutrition, Kyoto Prefectural University, Japan.
Ito
K
K
Nomura
H
H
Nakanishi
K
K
D000818:Animals; D019328:Buthionine Sulfoximine; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000031:analogs & derivatives / Q000172:deficiency* / Q000378:metabolism / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D010105:Oxygenases / Q000378:metabolism; D013827:Thiabendazole / Q000633:toxicity*
D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; C042431:S-ethyl glutathione; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D005978:Glutathione; D013827:Thiabendazole