Effect of glutathione depletion on Ifosfamide nephrotoxicity in rats

Abstract

Kidney injury is an important side effect of the chemotherapeutic agent ifosfamide in humans. Previous studies have shown that treatment with ifosfamide reduces kidney glutathione and that the toxicity of ifosfamide is enhanced in glutathione-depleted renal tubule cells in vitro. In this study, we examined the effect of glutathione depletion on ifosfamide nephrotoxicity in vivo using rats treated with the glutathione-depleting agent buthionine sulfoximine. Animals received 80 mg/kg ifosfamide intraperitoneally daily for three days with or without buthionine sulfoximine in drinking water. Buthionine sulfoximine produced a significant fall in renal glutathione content but did not affect kidney function. Ifosfamide-treated rats developed low-grade glucosuria, phosphaturia and proteinuria that worsened with concomitant buthionine sulfoximine therapy. These findings indicate that glutathione depletion exacerbates ifosfamide nephrotoxicity in rats and suggest that pharmacological methods for replenishing intracellular glutathione may be effective in ameliorating ifosfamide-induced renal injury.

Keywords: buthionine sulfoximine; glutathione; ifosfamide; kidney; toxic nephropathy.

Figure 1

Metabolism of ifosfamide.

Figure 2

Effect of ifosfamide and buthionine sulfoximine on urinary excretion rates of glucose (A), phosphate (B) and protein (C). Results are mean ± SEM. a, P<0.05 vs. corresponding pre-treatment result; b, P<0.05 vs. post-treatment ifosfamide group.

Figure 3

Effect of ifosfamide and buthionine sulfoximine on kidney glutathione concentrations. Results are mean ± SEM. a, P<0.05 vs. control group; b, P<0.05 vs. ifosfamide-treated group.