Oxidative stress as a mechanism of chronic cadmium-induced hepatotoxicity and renal toxicity and protection by antioxidants

The role of oxidative stress in chronic cadmium (Cd) toxicity and its preve ntion by cotreatment with antioxidants was investigated. Adult female Sprag ue-Dawley rats were injected sc with 5 mu mol CdCl2/kg/day, 5 times a week, for up to 22 weeks. Serum alanine amino transferase and lactate dehydrogen ase activities were elevated after 9 weeks of Cd administration, indicating hepatic damage. Renal toxicity, indicated by elevation in urinary lactate dehydrogenase activity and protein, was also observed around this time. Chr onic Cd administration resulted in a gradual rise in hepatic as well as ren al cortex glutathione levels. In spite of this, lipid peroxidation increase d in both tissues, particularly during the second half of the Cd exposure p eriod. Depletion of glutathione following buthionine sulfoximine administra tion at the end of Week 5, or inhibition of catalase by aminotriazole at th e end of Week 7, resulted in the development of acute nephrotoxicity within 6 h. Coadministration of antioxidants, N-acetylcysteine (50-100 mg/kg, sc) , or vitamin E (100-150 mg/kg, sc) with Cd, starting from the early phases of Cd exposure, controlled Cd-induced lipid peroxidation and protected the animals against hepatic as well as renal toxicity. A Japanese hepatoprotect ive drug, Stronger Neo-Minophagen C, containing glycyrrhizin, glycine, and cysteine, was also effective in reducing the chronic Cd nephrotoxicity. In conclusion oxidative stress appears to play a major role in chronic Cd-indu ced hepatic and renal toxicity since inhibition of components of the antiox idant defense system accelerated and administration of antioxidants protect ed against Cd toxicity. (C) 1999 Academic Press.