Oxygen free radicals are not the main factor in experimental gentamicin nephrotoxicity.

As a role for oxygen free radicals has been suggested in gentamicin (G) nephrotoxicity, we tested the hypothesis that exogenously administered glutathione (GSH), able to restore intracellular antioxidant potential, could be useful in reducing damage. Adult Sprague—Dawley rats were injected with saline (n = 30), subcutaneous (s.c.) G 100 (n = 23) and 150 mg/kg/day (n = 14), or s.c. G at the same dosages plus intraperitoneal (i.p.) GSH 1200 mg/kg/day (n = 24 and 14, respectively) for 7 days. In the G-100-day protocol, GSH-treated rats showed significantly lower renal G content (2.79 ± 0.8 vs. 3.61 ± 1.4 µg/mg prot) coupled with lower plasma urea (153 ± 79 vs. 188 ± 61 mg/dL) and creatinine levels (1.63 ± 1 vs. 2.45 ± 1 mg/dL). As to renal oxidant/antioxidant balance, local GSH was increased (0.32 ± 0.01 vs. 0.19 ± 0.01 µg/mg prot) while lipid peroxidation, determined-by production of thiobarbituric acid reactive substances (TBARS), was decreased (0.35 ± 0.02 vs. 0.52 ± 0.02 nmol/mg prot). In the G-150-mg protocol, GSH-treated rats showed no differences in renal gentamicin content or in blood urea and creatinine levels, in spite of a significantly lower renal TBARS production and a significantly higher GSH content. Urine enzyme excretion did not significantly change in GSH-treated vs. not-GSH-treated rats in both protocols. We conclude that: (a) GSH interferes with G nephrotoxicity mainly via a reduction in G uptake; (b) the oxidative renal stress is not crucial in inducing renal damage. In fact, when increased G dosages blunt the ability of GSH in reducing G uptake, no substantial protection is demonstrated.