Evaluation of oxidative stress-mediated cytotoxicity and genotoxicity of copper and flubendiamide: amelioration by antioxidants in vivo and in vitro.

Abstract

Present study was designed to evaluate toxic effects of copper (Cu) (@ 33 mg/kg b.wt.) and flubendimide (Flb) (@ 200 mg/kg b.wt.) alone and/or in combination on blood-biochemical indices, oxidative stress, and drug metabolizing enzymes (DMEs) in vivo in male Wistar rats following oral exposure continuously for 90 days and their immunotoxic (cyto-genotoxic and apoptotic) potential in vitro on thymocytes. In in vivo study, ameliorative potential of α-tocopherol was assessed, whereas α-tocopherol, curcumin, resveratrol, and catechin were evaluated for protective effect in vitro. Significantly (P < 0.05) increased AST activity and increment in total bilirubin, uric acid, creatinine, and BUN levels; however, reduction in total protein, GSH content, reduced activities of SOD and GST, and increased lipid peroxidation and GPx activity with severe degenerative changes in histopathological examination of liver and kidney in group of Cu and Flb were observed. Treatment with α-tocopherol improved biochemical variables, redox status, and histoarchitecture of liver and kidney tissues. Reduced hepatic CYP₄₅₀, CYP_b5, APH, UGT, and GST activities observed in both Cu and α-tocopherol alone and their combination groups, whereas significant increment in Flb alone, while α-tocopherol in combination with xenobiotics improved the activities of hepatic DMEs. Primary cell culture of thymocytes (10⁶ cells/ml) exposed to Cu and Flb each @ 40 μM increased TUNEL_+ve cells, micronuclei induction, DNA shearing, and comet formation establishes their apoptotic and genotoxic potential, whereas treatment with antioxidants showed concentration-dependent significant reduction and their order of potency on equimolar concentration (10 μM) basis is: curcumin > resveratrol > catechin = α-tocopherol.