Effect of buthionine sulfoximine on N-(3,5-dichlorophenyl)-2-hydroxysuccinimide and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid nephrotoxicity.
N-(3,5-Dichlorophenyl)succinimide (NDPS) is an agricultural fungicide which induces acute tubular necrosis as its primary toxicity. Two NDPS metabolites, N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (NDHSA) previously have been shown to be more potent nephrotoxicants than NDPS. In addition, buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, was found to attenuate NDPS-induced nephrotoxicity. The purpose of this study was to examine the effects of BSO pretreatment on NDHS- and NDHSA-induced nephrotoxicity. Male Fischer-344 rats (4 rats/group) were administered intraperitoneally (i.p.) BSO (890 mg/kg) 2 h before NDHS or NDHSA (0.1 or 0.2 mmol/kg, i.p.) or vehicle (sesame oil, 2.5 ml/kg), and renal function monitored at 24-h intervals for 48 h. BSO pretreatment markedly attenuated NDHSA (0.1 or 0.2 mmol/kg)-induced effects on the renal functional parameters monitored. BSO pretreatment also markedly reduced NDHS (0.1 mmol/kg)-induced renal effects. However, NDHS (0.2 mmol/kg) nephrotoxicity was attenuated to a lesser extent than NDHS (0.1 mmol/kg) nephropathy. These results indicate that glutathione is an important mediator of NDPS metabolite nephrotoxicity and suggests that BSO did not attenuate NDPS nephropathy by inhibiting NDPS biotransformation to NDHS or NDHSA.
Rankin
G O
GO
Department of Pharmacology, Marshall University School of Medicine, Huntington, WV 25755-9310.
Teets
V J
VJ
Nicoll
D W
DW
Brown
P I
PI
D000818:Animals; D019328:Buthionine Sulfoximine; D005659:Fungicides, Industrial / Q000633:toxicity*; D005978:Glutathione / Q000502:physiology; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013386:Succinates / Q000633:toxicity*; D013388:Succinimides
D005659:Fungicides, Industrial; D013386:Succinates; D013388:Succinimides; C070526:N-(3,5-dichlorophenyl)-2-hydroxysuccinimide; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; C070595:N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid; D005978:Glutathione