The role of paraoxonase polymorphisms in the induction of micronucleus in paraoxon-treated human lymphocytes.

Human paraoxonase-1 (PON1) is a high-density lipoprotein-associated enzyme that has a role in the detoxification of organophosphorus compounds by hydrolyzing the bioactive oxons. PON1 polymorphims are responsible, at least in part, for the variation in the catalytic activity and expression of the enzyme and have been associated with susceptibility to organophosphorus pesticide toxicity, mainly neurotoxicity. The aim of this study was to determine whether paraoxon induced micronuclei and to examine the role of PON1 polymorphism in paraoxon's genotoxic potential. First, dose finding cytogenetic experiments were performed on lymphocyte cultures from three donors and a range of paraoxon concentration (1-25 microM) were tested. In a second set of experiments, 5 microM paraoxon was added to blood cultures of 11 donors with two different PON1 haplotypes (PON T(-108)M(55)Q(192) with low activity and haplotype PON C(-108)L(55) R(192) with high activity, referred to as PON1QQ and as PON1 RR, respectively). Because PON1 is present in blood, the effect of adding 5 microM paraoxon and 70 microl of autologous plasma to lymphocyte cultures also was examined. Paraoxon had no effect on cell viability, but caused a significant dose-dependent increase in MN frequency. The basal MN frequencies were similar on QQ and RR genotypes. A significant difference was observed in the MN frequency only in lymphocytes from individuals with the QQ genotype treated with 5 microM paraoxon and the autologous plasma did not modify these effects. The results obtained in this study suggest that PON1 genotype might have an important role in the identification of individuals at risk for cancer development due to occupational exposure to pesticides.