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 peroxidation, modulates calcium homeostasis, decreases membrane fluidity, and increases nuclear DNA damage. Little information is available on the neurotoxicity of endrin. The effects of endrin on lipid peroxidation, DNA damage, and regional distribution of catalase activity were assessed in rat brain and liver 24 h following an acute oral dose of 4.5 mg endrin/kg. Lipid peroxidation associated with whole brain mitochondria increased 2.4-fold, whereas microsomal lipid peroxidation increased 2.8-fold following endrin administration. Lipid peroxidation also increased 2.0-fold both in hepatic mitochondria and microsomes. Catalase 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) was observed in endrin-treated rats. Pretreatment of rats intraperitoneally with the lazaroid U74389F (16-desmethyl tirilazad) (10 mg/kg in two doses) attenuated the biochemical consequences of endrin-induced oxidative stress. The administration of U74389F in citrate buffer (pH 3.8) provided better protection than administering the lazaroid in corn oil, decreasing endrin-induced lipid peroxidation by 50-80% and DNA-SSB by approximately 72% in liver and 85% in brain, while ameliorating the suppressed catalase activity. The data suggest an involvement of an oxidative stress in the neurotoxicity and hepatotoxicity induced by endrin, which can be attenuated by the lazaroid U74389F.
Bagchi
M
M
Department of Pharmaceutical and Administrative Sciences, Creighton University Health Sciences Center, Omaha, NE, USA.
Ghosh
S
S
Bagchi
D
D
Hassoun
E
E
Stohs
S J
SJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D002374:Catalase / Q000032:analysis / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004732:Endrin / Q000494:pharmacology*; D005260:Female; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D011281:Pregnatrienes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014018:Tissue Distribution
D000975:Antioxidants; D011281:Pregnatrienes; D017392:Thiobarbituric Acid Reactive Substances; C074965:U 74389F; D002374:Catalase; D004732:Endrin