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

Abstract

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.

Antigenotoxic Effect of Curcumin and Carvacrol against Parathion Induced DNA Damage in Cultured Human Peripheral Blood Lymphocytes and Its Relation to GSTM1 and GSTT1 Polymorphism

“…Methyl parathion was also found genotoxic to human peripheral blood lymphocytes under in vitro conditions [ 22 ]. Rojas-García et al [ 23 ] reported the dose dependent increase in micronucleus in peripheral human blood lymphocytes with paraoxon (an active metabolite of parathion). They treated the peripheral human blood lymphocytes with range of 1–25 μ M concentrations of paraoxon and found dose dependent DNA damage.…”

Epigenetic Regulation of Centromere Chromatin Stability by Dietary and Environmental Factors

“…A comprehensive review on the genotoxic effect of commonly used pesticides by persons in the work place and those employed in the chemical industry was conducted by Bolognesi et al (5), highlighting the importance of genotoxic biomonitoring in human populations who might be at a greater risk of cancer. Interestingly, many of the studies on increased micronucleus frequency in pesticideexposed populations have established the incidence of specific polymorphisms within Paraoxonase 1 (PON1), an enzyme that detoxifies organophosphates (5,119). This is an example of a gene-environment interaction that could help explain the modification of the relation between occupational exposures and aneuploidic events by genotype.…”

Human Biotransformation Pathway of Temephos Using an In Silico Approach

“…These limitations include some aspects related to enzyme kinetics and pharmacokinetics, which can be modified by internal and external factors, and physio-pathological conditions that are yet unknown for temephos. For example, López-Flores et al (2009) reported that chronic exposure to OPs causes a depletion of the PON activity; this exacerbates cholinergic effects associated with oxon formation. , In the same sense, the polymorphism of PON modulates the magnitude of DNA damage caused by OP exposure and the possible inhibition of some CYP isoforms by temephos, as has been described for other OPTs, such chlorpyrifos, forate, and fonofos. − All these factors could modify the rate of each reaction and change the final proportion of metabolites formed. The biotransformation pathway proposed in this work is like a map in that if something blocks a route, another possible route, or reaction, will be utilized.…”