Stereospecificity in the cytotoxic action of hexachlorocyclohexane isomers.
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 (alpha, beta, gamma, and delta), delta isomer being most toxic and beta 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 Ca(2+),Mg(2+)-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 delta and lowest by beta. Further, this study demonstrates for the first time a clear link between Na(+),K(+)-ATPase, i[Ca(2+)] level, and oxidative stress in HCH-induced cytotoxicity.
Srivastava
Anup
A
Department of Pathology, Center for Free Radical Biology, 901, 19th St. S., Rm #347, University of Alabama at Birmingham, Birmingham, AL 35294, USA. anup@uab.edu
Shivanandappa
T
T
D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy; D053148:Caspase 3 / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D001556:Hexachlorocyclohexane / Q000737:chemistry / Q000633:toxicity*; D007306:Insecticides / Q000737:chemistry / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D019255:NADPH Oxidases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013237:Stereoisomerism
D007306:Insecticides; D017382:Reactive Oxygen Species; D001556:Hexachlorocyclohexane; D007770:L-Lactate Dehydrogenase; D019255:NADPH Oxidases; D053148:Caspase 3; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione