CYP2E1 INDUCTION and Oxidative STRESS IN CEREBELLAR Granule Neurons

Although CYP content in brain is low as compared to hepatic levels, the bioactivation of xenobiotics into oxidants or radicals within the brain is relevant, considering the limited regenerative capacity of the neurons and its vulnerability to oxidative damage. CYP2E1 is considered the most important isoform that is able to form reactive oxygen species leading to lipid peroxidation and cell death. The aim of this study was to determine if CYP2E1 induction by xenobiotics is capable to induce oxidative damage. Exposition of primary neuron cultures to different inducers of CYP2E1 (ethanol, isoniazid and acetone) was traduced in a CYP2E1 increase as determined by immunocitochemistry. This increase was accompanied by a slight production of reactive oxygen species (ROS) and cell death. On the other hand, treatment of cells with buthionine sulfoximine, an agent that reduces glutathione levels, resulted in a significant increase in ROS and cell death after isoniazid treatment. This effect was reverted by simultaneous exposure to diallyl sulfide (CYP2E1 inhibitor) or to the antioxidant MnPTyP. These results suggest that CYP2E1 is a potential promoter of neuronal oxidative damage. Further experiments are planned to elucidate the mechanisms by which CYP2E1 induction could progress in oxidative brain toxicity. .