In vitro and in vivo effects of phenolic antioxidants against cisplatin-induced nephrotoxicity

We have investigated the effect of phenolic antioxidants on cisplatin-induc ed cytotoxicity in vero (African Green Monkey Kidney) cells and in rat rena l cortical slices in vitro, and on cisplatin-induced nephrotoxicity in rats in vivo, Incubation of cisplatin with vero cells resulted in time- and con centration-dependent cytotoxicity, as characterized by decreased tryphan bl ue exclusion (TBE) and increased release of lactate dehydrogenase (LDH) int o the medium. Cisplatin also caused reduction of glutathione (GSH) in a con centration-dependent manner. In the rat renal cortical slices model, incuba tion of cisplatin for 120 min caused an increase in malondialdehyde (MDA), a decrease in GSH and inhibited p-aminohippurate (PAH) uptake in a concentr ation-dependent manner. Among phenolic antioxidants, isoeugenol (IG) was fo und to be more active against cisplatin-induced cytotoxicity in vero cells as well as in rat renal cortical slices than eugenol (EG) and dehydrozinger one (DZ), However none of the test compounds were able to arrest the reduct ion of the GSH content induced by cisplatin in either the vero cells or the renal cortical slice model, Administration of cisplatin (3 mg/kg) i.p. to rats resulted in significant reduction of body weight, and elevation of blo od urea nitrogen (BUN) and serum creatinine, Treatment with IG 10 mg/kg i.p . 1 h before cisplatin resulted in partial but significant protection again st the cisplatin-induced reduction of body weight, and elevation of BUN and serum creatinine, the protection being 34, 46, and 62%, respectively, EG a nd DZ (10 mg/kg, i.p.) were found to be inactive in vivo. Because IG is a p otent free radical scavenger and protects against cisplatin-induced toxicit iy, the present results have many clinical implications in cisplatin chemot herapy and thus warrants further investigation.