This study demonstrates that cisplatin ototoxicity depends on dietary factors and correlates with decreased levels of cochlear glutathione and serum albumin. After 12 days of injections, cisplatin (1 mg/kg body weight, s.c.) caused a small hearing loss in guinea pigs fed a regular, full-protein diet (9 +/- 6 dB at 8 kHz and 10 +/- 9 dB at 18 kHz) but a significantly higher hearing loss in animals on a low-protein diet (23 +/- 17 dB at 8 kHz and 32 +/- 23 dB at 18 kHz). Animals on the low-protein diet gained significantly less weight than those on the regular diet, and cisplatin treatment lowered the weight gain in both groups. The low-protein diet also significantly reduced cochlear glutathione levels from 180 +/- 50 to 90 +/- 21 nmol/mg protein and serum albumin from 2.32 +/- 0.04 to 1.75 +/- 0.06 g/dl. Cisplatin treatment tended to decrease glutathione and serum albumin in animals on a full-protein diet but not on the low-protein diet. Renal function was assessed by measuring blood urea nitrogen (BUN) and serum creatinine. While BUN and creatinine values indicated some cisplatin-induced nephrotoxicity, there was no correlation with the severity of ototoxicity. Furthermore, serum platinum levels did not differ between animals on either diet, ruling out a potential influence of altered pharmacokinetics on ototoxicity. These results suggest that the metabolic state of the animal is a risk factor for cisplatin ototoxicity.