Adaptation to nephrotoxic chemicals

Rats given gentamicin chronically become resistant to its nephrotoxic effects. To further explore this adaptation to nephrotoxicity, we gave male rats gentamicin 40 mg/kg/day for 12 days, then 80 mg/kg/day for 24 days. We then challenged them with 110 mg/kg/day of gentamicin for 9 days. Spermine was given 16 mg/kg/day for 42 days, then gentamicin challenge at 60 mg/kg/day for 9 days. Gossypol was given at 6 mg/kg/day for 19 days, then gentamicin at 60 mg/kg/day for 21 days. A fourth group of rats (controls) received 0.5 ml saline daily for 42 days and then received gentamicin 60 mg/kg/day for 9 days. Urine N-acetyl-beta-glucosaminidase (NAG) was measured 3 times weekly and serum creatinine was measured 5 times during the study. Each drug-treated rat increased its urine NAG from baseline values. After a period of drug administration, all NAG values returned to the predrug values. Then all animals were given gentamicin daily. NAG values increased 20-fold in the animals previously treated with saline but did not rise in the other groups. The serum creatinine frequently but not always changed in parallel with the NAG values. These observations indicate that adaptation to these nephrotoxic substances occurs and that cross-resistance to gentamicin is produced by spermine and gossypol.