title: Paraoxonase-1 genetic polymorphisms and susceptibility to DNA damage in workers occupationally exposed to organophosphate pesticides.
abstract: 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.
authors.affiliation: Division of Biochemistry & Biotechnology, National Centre for Disease Control, 22, Sham Nath Marg, Delhi-110054, India.
authors.forename: Satyender
authors.initials: S
authors.lastname: Singh
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.forename: Sachin
authors.initials: S
authors.lastname: Thakur
authors.forename: Basu Dev
authors.initials: BD
authors.lastname: Banerjee
authors.forename: Rajender Singh
authors.initials: RS
authors.lastname: Rautela
authors.forename: Shyam Sunder
authors.initials: SS
authors.lastname: Grover
authors.forename: Devendra Singh
authors.initials: DS
authors.lastname: Rawat
authors.forename: Syed Tazeen
authors.initials: ST
authors.lastname: Pasha
authors.forename: Sudhir Kumar
authors.initials: SK
authors.lastname: Jain
authors.forename: Rattan Lal
authors.initials: RL
authors.lastname: Ichhpujani
authors.forename: Arvind
authors.initials: A
authors.lastname: Rai
mesh_terms: D000328:Adult; D043303:Aryldialkylphosphatase / Q000097:blood / Q000235:genetics*; D003430:Cross-Sectional Studies; D004249:DNA Damage / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure / Q000009:adverse effects*; D009943:Organophosphorus Compounds / Q000097:blood / Q000633:toxicity; D010575:Pesticides / Q000097:blood / Q000633:toxicity*; D011110:Polymorphism, Genetic / Q000235:genetics*
chemical_list: D009943:Organophosphorus Compounds; D010575:Pesticides; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human