Abstract: Thymoquinone (TQ) is the major biologically active component (about 54%) of volatile oil of black seed that has been shown to exert anti-inflammatory, antioxidant and anti-neoplastic effects both in vitro and in vivo. TQ induces apoptosis, disrupts mitochondrial membrane potential and triggers the activation of caspases 8, 9 and 3 in myeloblastic leukaemia HL-60 cells. Although TQ acts as antioxidant and is found to inhibit inflammation in animal models and culture systems, it can also cause glutathione depletion thus acting as a prooxidant. It has been suggested that TQ may be metabolized to reactive species and increase oxidative stress that contributes to the depletion of antioxidant enzymes and damage to DNA in hepatocytes treated with high concentrations of the compound. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that TQ and its metabolic products have LUMO-HOMO energy differences ranging from 3.8 to 5.4 eV indicating that the compounds would be moderately inert kinetically with THY being most inert.

The molecular surfaces of TQ and DTQ are found to possess significant amounts of positively charged electron-deficient regions so that they may be subject to nucleophilic attacks by glutathione and nucleobases in DNA, thus causing cellular toxicity due to glutathione depletion and DNA damage due to oxidation of nucleobases.


KEY WORDS: Thymoquinone, black seed, antioxidant, apoptosis, molecular modeling.