PROTECTIVE EFFECTS OF LAZAROID U74389F (16-DESMETHYL TIRILAZAD) ON ENDRIN-INDUCED LIPID-PEROXIDATION AND DNA-DAMAGE IN BRAIN AND LIVER AND REGIONAL DISTRIBUTION OF CATALASE ACTIVITY IN RAT-BRAIN

Endrin, a poly-halogenated cyclic hydrocarbon, induces hepatic lipid p eroxidation, modulates calcium homeostasis, decreases membrane fluidit y, and increases nuclear DNA damage. Little information is available o n the neurotoxicity of endrin. The effects of endrin on lipid peroxida tion, DNA damage, and regional distribution of catalase activity were assessed in rat brain acid liver 24 h following an acute oral dose of 4.5 mg endrin/kg. Lipid peroxidation associated with whole brain mitoc hondria increased 2.4-fold, whereas microsomal lipid peroxidation incr eased 2.8-fold following endrin administration. Lipid peroxidation als o increased 2.0-fold both in hepatic mitochondria and microsomes. Cata lase activity decreased 24% in the hypothalamus, 23% in the cortex, 38 % in the cerebellum, and 11% in the brain stem in response to endrin. A 4.3-fold increase in brain nuclear DNA-single strand breaks (SSB) wa s observed in endrin-treated rats. Pretreatment of rats intraperitonea lly with the lazaroid U74389F (16-desmethyl tirilazad) (10 mg/kg in tw o doses) attenuated the biochemical consequences of endrin-induced oxi dative stress. The administration of U74389F in citrate buffer (pH 3.8 ) provided better protection than administering the lazaroid in corn o il, decreasing endrin-induced lipid peroxidation by 50-80% and DNA-SSB by approximately 72% in liver and 85% in brain, while ameliorating th e suppressed catalase activity. The data suggest an involvement of an oxidative stress in the neurotoxicity and hepatotoxicity induced by en drin, which can be attenuated by the lazaroid U74389F.