Division of Biochemistry & Biotechnology, National Centre for Disease Control, 22, Sham Nath Marg, Delhi-110054, India.
Toxicol Appl Pharmacol. 2011 Apr 15;252(2):130-7. doi: 10.1016/j.taap.2011.01.014. Epub 2011 Feb 1.
Human paraoxonase 1 (PON1) is a lipoprotein-associated enzyme involved in the detoxification of organophosphate pesticides (OPs) by hydrolyzing the bioactive oxons. Polymorphisms of the PON1 gene are responsible for variation in the expression and catalytic activity of PON1 enzyme. In the present study, we have determined (a) the prevalence of two common PON1 polymorphisms, (b) the activity of PON1 and acetylcholinesterase enzymes, and (c) the influence of PON1 genotypes and phenotypes variation on DNA damage in workers exposed to OPs. We examined 230 subjects including 115 workers exposed to OPs and an equal number of normal healthy controls. The results revealed that PON1 activity toward paraoxon (179.19±39.36 vs. 241.52±42.32nmol/min/ml in controls) and phenylacetate (112.74±17.37 vs. 134.28±25.49μmol/min/ml in controls) was significantly lower in workers than in control subjects (p<0.001). No significant difference was observed in the distribution of genotypes and allelic frequencies of PON1(192)QR (Gln/Arg) and PON1(55)LM (Leu/Met) in workers and control subjects (p>0.05). The PON1 activity toward paraoxonase was found to be significantly higher in the R/R (Arg/Arg) genotypes than Q/R (Gln/Arg) and lowest in Q/Q (Gln/Gln) genotypes in both workers and control subjects (p<0.001). For PON1(55)LM (Leu/Met), PON1 activity toward paraoxonase was observed to be higher in individuals with L/L (Leu/Leu) genotypes and lowest in individuals with M/M (Met/Met) genotypes in both groups (p<0.001). No influence of PON1 genotypes and phenotypes was seen on the activity of acetylcholinesterase and arylesterase. The DNA damage was observed to be significantly higher in workers than in control subjects (p<0.05). Further, the individuals who showed least paraoxonase activity i.e., those with (Q/Q [Gln/Gln] and M/M [Met/Met]) genotypes showed significantly higher DNA damage compared to other isoforms in workers exposed to OPs (p<0.05). The results indicate that the individuals with PON1 Q/Q and M/M genotypes are more susceptible toward genotoxicity. In conclusion, the study suggests wide variation in enzyme activities and DNA damage due to polymorphisms in PON1 gene, which might have an important role in the identification of individual risk factors in workers occupationally exposed to OPs.
人对氧磷酶 1（PON1）是一种脂蛋白相关酶，通过水解生物活性氧膦来解毒有机磷农药（OPs）。PON1 基因的多态性导致 PON1 酶的表达和催化活性的变化。在本研究中，我们确定了（a）两种常见的 PON1 多态性的流行率，（b）PON1 和乙酰胆碱酯酶的活性，以及（c）PON1 基因型和表型变异对接触 OPs 的工人的 DNA 损伤的影响。我们检查了 230 名受试者，包括 115 名接触 OPs 的工人和 115 名正常健康对照者。结果表明，与对照组相比（对照组为 241.52±42.32nmol/min/ml），接触 OPs 的工人的 PON1 对paraoxon（179.19±39.36）和苯乙酸（112.74±17.37）的活性明显降低（p<0.001）。在工人和对照组中，PON1(192)QR（Gln/Arg）和 PON1(55)LM（Leu/Met）的基因型和等位基因频率分布无显著差异（p>0.05）。PON1 对 paraoxonase 的活性在 R/R（Arg/Arg）基因型中明显高于 Q/R（Gln/Arg），而在 Q/Q（Gln/Gln）基因型中最低，在工人和对照组中均如此（p<0.001）。对于 PON1(55)LM（Leu/Met），PON1 对 paraoxonase 的活性在 L/L（Leu/Leu）基因型的个体中较高，而在 M/M（Met/Met）基因型的个体中最低，两组均如此（p<0.001）。PON1 基因型和表型对乙酰胆碱酯酶和芳基酯酶的活性没有影响。与对照组相比，工人的 DNA 损伤明显更高（p<0.05）。此外，在接触 OPs 的工人中，与其他同工酶相比，具有最低的对氧磷酶活性的个体（即具有（Q/Q [Gln/Gln]和 M/M [Met/Met]）基因型的个体）的 DNA 损伤明显更高（p<0.05）。结果表明，PON1 Q/Q 和 M/M 基因型的个体对遗传毒性更敏感。总之，本研究表明由于 PON1 基因的多态性导致酶活性和 DNA 损伤广泛变化，这可能在识别职业接触 OPs 的工人的个体危险因素方面具有重要作用。
