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 (�, �, �, and �), � isomer being most toxic and � 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 �
and lowest by �. Further, this study demonstrates for the first time a clear link between Na+,K+-ATPase,
i[Ca2+] level, and oxidative stress in HCH-induced cytotoxicity.