Studies on the Fate of Thiabendazole (TBZ) in Mice. IV. Nephropathy of Male and Female Mice Induced after Oral Administration of TBZ

Abstract

Induction of nephropathy by thiabendazole (TBZ) was compared between male and female mice of 5 and 11 week-old. TBZ was suspended in olive oil and mice were given, by stomach tube, a single dose of 1300 mg/kg TBZ only (TBZ group), and 350 or 1300 mg/kg TBZ 1 h after intraperitoneal injection of L-buthionine sulfoximine (BSO), an inhibitor of γ-glutamylcysteine synthetase, (BSO-TBZ350 or BSO-TBZ1300 groups). As controls, mice were given olive oil only in the same manner (control or BSO-control groups). Animals were killed 1, 6 and 24 h after administration of TBZ. Blood urea nitrogen (BUN) and enzyme activities such as alkaline phosphatase (ALP), leucine aminopeptidase (LAP), γ-glutamyl transpeptidase (γ-GTP) and N-acetyl-β-D-glucosaminidase (NAG) in the kidney and urine were determined. Preparations of kidney tissues were also examined by microscopy. Five of 6 males in 11 week-old BSO-TBZ350 group and 6 of 8 females in 11 week-old BSO-TBZ1300 group died within 24 h after TBZ-administration. In mice of male and female BSO-TBZ groups, the relative kidney weight increased significantly, as compared to controls. BUN increased in TBZ and also BSO-TBZ groups 6 h after administration of TBZ. As specific enzyme activities in the kidney, ALP and γ-GTP in 5 week-old males of TBZ group, and ALP in 5 week-old males and 11 week-old females, LAP in 11 week-old females and γ-GTP in 5 and 11 week-old males of BSO-TBZ group decreased significantly. NAG also decreased in 5 week-old males of BSO-TBZ group. In urine of 5 week-old mice, the concentration of protein increased both in male and female animals, and specific enzyme activities such as ALP, γ-GTP and NAG increased in male mice of BSO-TBZ group. Marked dilatation of proximal tubules were observed microsopically at 24 h in TBZ group and at 6 h in BSO-TBZ350 group. These results indicate that the nephrotoxic effect of TBZ in mice increased with glutathione deficiency. It was demonstrated that nephrotoxicity of TBZ was stronger in male mice than in female mice, and in 5 week-old than 11 week-old males of TBZ group and in 11 week-old than 5 week-old males of BSO-TBZ group.