Polymorphism in cytochrome P450 2D6-mediated activation of Malathion in rats.

Organophosphorus insecticides are widely used in agriculture although they are potentially toxic to humans for their ability to inhibit the enzyme acetylcholinesterase, which hydrolyzes the neurotransmitter acetylcholine at nerve synapse and neuro-muscular junction. They are used as phosphorothioate, to be converted in vivo to the active oxygenated form; this process of desulphuration is mediated by cytochrome P450 enzymes1. In the present study we evaluated the potential involvement of CYP2D6 in malathion biotransformation to the active form malaoxon, which even seems to induce free radical generation and lipid peroxidation2. CYP2D6 polymorphism may be important in understanding why certain individuals (extensive metabolizers) appear to be at greater risk from exposure to some organophosphorus compounds than others (poor metabolizers, 5-10 % of Caucasians)3. We used quinine (12.5 mg/kg, p.o. for 3 days) as a specific inhibitor of CYP2D6 in male Wistar rats4. The influence on malathion activation was verified in vivo evaluating the inhibition of serum acetylcholinesterase. We also investigated the effects of malathion exposure (1g/kg p.o.) on oxidative stress by assessing lipid peroxidation as malondialdehyde production (MDA), reduced glutathione (GSH) consumption, glutathione-S-transferase (GST) enzymatic activity, variation of catalase (CAT) and superoxide dismutase (SOD) in liver homogenate of rats treated with quinine and malathion. Acetylcholinesterase inhibition and lipid peroxidation determined by malathion were significantly reduced by quinine treatment, which also reduced GSH consumption and GST, CAT and SOD increment due to malathion. In conclusion, these data confirm that oxidative stress is involved in the toxicity of malathion and support the hypothesis that CYP2D6 has an important role in the bioactivation pathway of this pesticide. As a consequence, the polymorphism of CYP2D6 influences individual susceptibility to exposure to malathion.