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There are many conflicting reports around the phenytoin (PHT)-induced genotoxic effect especially in the in-vitro studies. PHT was claimed to cause genotoxic effect by the oxidative stress of its metabolic intermediates. However, by reviewing the distribution and activity of the enzymes responsible for PHT metabolism, we found that PHT is rarely metabolized by human lymphocytes. So that, we will use isolated cultured human lymphocytes to determine which is genotoxic, PHT itself or its metabolites? PHT 60 μg/ml were added to lymphocytes before and after metabolic activation by S9. Also, this study will investigate the possible antioxidant genoprotective effects of Thymoquinone (TQ) 1 μM and Curcumin (CMN) 15 μM on the chromosomal injury induced by PHT or its metabolites. After the end of culture period, the effects of PHT on the lymphocytes were investigated by measuring levels of chromosomal aberrations (CAs); mitotic index (MI); reduced glutathione (GSH); malondialdehyde (MDA); and 8-hydroxydeoxyguanosine (8-OH-dG). Only PHT after metabolic activation caused oxidative genotoxic effects which were significantly ameliorated by TQ more than CMN. Hence, the present study is the first to record that PHT without metabolic activation in isolated human lymphocytes from non epileptic donors cause dose dependant direct toxic effect rather than genotoxic effect.   Key words: Phenytoin, thymoquinone, curcumin, genotoxic

Phenytoin: Is it genotoxic in isolated cultured human lymphocytes without metabolic activation by S9?