In vitro studies on the activation of the organophosphate pesticide Malathion by Cytochrome P450 2D6 in rat liver mcrosomes

Malathion is one of the phosphorothioate pesticides mostly used in agriculture and public health programmes. It has been detected in the environment as contaminant of drinking water and pesticide residues foodstuff; thus, human exposure to malathion may occur through occupational settings, agricultural workers or pesticide applicators, as well as via a variety of environmental sources. Malathion is a weak acetylcholinesterase inhibitor unlike its metabolite, malaoxon, which is a potent anticholinesterase agent. Moreover, recent studies raised concerns over the potential of malathion and its metabolite to cause genetic damage as strongly positive alkylating agents. As well known the activation of malathion to the oxygen analogue malaoxon occurs in vivo by the oxidative desulfuration of the parent compound and it is mediated by the cytochromes P450 (CYP), even if the specific isoform involved in the metabolizing process is not yet known. In the present in vitro study we used quinine, a specific inhibitor of CYP2D6, to investigate if malathion activation in rat liver microsomes is catalysed by CYP2D6 subfamily. If this hypothesis is confirmed proving that CYP2D6 is involved in malathion activation, its inhibition by quinine may show a reduction of the oxon genotoxicity on human leucocytes in the single cell gel electrophoresis (comet assay), which is a sensitive genotoxicity test able to investigate DNA damage detecting single strand breakage. In the present study the results show that acetylcholinesterase inhibition and genotoxicity determined by malathion were significantly reduced by quinine treatment, due to a decrement of malaoxon production, suggesting that CYP2D6 may have an important role in the bioactivation pathway of this pesticide. According to the knowledge that CYP2D6 is characterized by a genetic polymorphism, it follows that if CYP2D6 is responsible of malathion activation the risk deriving from exposure to malathion may be dependent on the genotype of the population. As a consequence, the polymorphism of CYP2D6 influences individual susceptibility to exposure to malathion.