Genotossicità ed attivazione di antiparassitari organofosforici e carbammati da parte del citocromo P450 2D6

The role of the polymorphic cylochrome P450 (CYP) 2D6 isoform in catalysing the oxidative biotransformation of the organophosphate pesticide chlorpyriphos and the carbamate aldicarb into structures that inhibit cholinesterase and induce genotoxicity has been investigated in microsomal fraction, using quinine as a specific chemical inhibitor of CYP 2D6. Pesticides were incubated with rat liver microsomes and production of anticholinergic active metabolites was investigated by the inhibition of human serum cholinesterase. Compared to microsomes incubated without quinine, where cholinesterase activity was inhibited to a mean 53% (chlorpyriphos) and 57% (aldicarb) of control the introduction of P450 2D6 inhibitor quinine into microsomal incubation mixture reduced cholinesterase activity to 72% of control for chlorpyriphos and to 27% for aldicarb, suggesting that P450 2D6 is involved in the activation of chlorpyriphos but does not influence aldicarb toxicity on acetylcholinesterase. Moreover, the potential genotoxicity of these compounds was evaluated by single cell gel electrophoresis (comet assay) on human leucocytes. DNA fragmentation compared to control was markedly increased after incubation with aldicarb plus quinine, conforming that the parent compound is more toxic than the products of CYP metabolism; conversely, DNA damage after incubation with chlorpyriphos was sensibly reduced by quinine indicating the metabolic activation of this pesticide by CYP 2D6. These data suggest that polymorfism of CYP 2D6 can influence the toxicity of organophosphate but not of carbamate pesticides.