Stereospecificity in the cytotoxic action of hexachlorocyclohexane isomers |
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| Authors: | Anup Srivastava T Shivanandappa |
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| Institution: | 1. Department of Pathology, Center for Free Radical Biology, 901, 19th St. S., Rm #347, University of Alabama at Birmingham, Birmingham, AL 35294, USA;2. Department of Food Protectants and Infestation Control, Central Food Technological Research Institute, Mysore 570020, Karnataka, India;1. Department of Chemistry, Federal University of Lavras, P.O. Box 3037, 37200-000 Lavras, MG, Brazil;2. Chemistry Institute, State University of Campinas, P.O. Box 6154, 13083-970 Campinas, SP, Brazil;3. Department of Chemistry, Federal University of Viçosa, 36570-900 Viçosa, MG, Brazil;1. ICAR-National Centre for Integrated Pest Management, PUSA Campus, New Delhi 12, India;2. Land and Water, CSIRO, Waite Campus, Urrbrae, South Australia 5064, Australia;1. Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA;2. Department of Neuroscience, University of Parma, Parma, Italy;1. Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, United States;2. Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, 32610, United States |
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| Abstract: | Hexachlorocyclohexane (HCH) is a highly recalcitrant organochlorine insecticide known for its chronic toxicity. In spite of many isolated studies a clear mechanism of cytotoxic action of HCH and the structure–toxicity relationship of its isomers is not well understood. We have investigated the toxicity of HCH isomers and its mechanism in Ehrlich Ascites tumor (EAT) cells. Our studies show differential cytotoxicity of HCH isomers (α, β, γ, and δ), δ isomer being most toxic and β the least. HCH-induced cell death was associated with induction of reactive oxygen species (ROS) formation, lipid peroxidation (LPO), and depletion of glutathione (GSH). The increase in oxidative stress was linked with increased NAD(P)H oxidase activity. HCH inhibited Na+,K+-ATPase, which could be involved in raising the intracellular calcium and increased Ca2+,Mg2+-ATPase activity. HCH lead to apoptotic as well as necrotic cell death as it was marked by increased caspase-3 activity and lactate dehydrogenase (LDH) leakage, respectively. Based on the results it is concluded that the HCH isomers inflict differential cytotoxicity which was highest by δ and lowest by β. Further, this study demonstrates for the first time a clear link between Na+,K+-ATPase, iCa2+] level, and oxidative stress in HCH-induced cytotoxicity. |
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