title: Role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to organophosphate pesticides.
abstract: Organophosphate pesticides (OPs) are primarily metabolized by several xenobiotic metabolizing enzymes (XMEs). Very few studies have explored genetic polymorphisms of XMEs and their association with DNA damage in pesticide-exposed workers. The present study was designed to determine the role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to OPs. We examined 284 subjects including 150 workers occupationally exposed to OPs and 134 normal healthy controls. The DNA damage was evaluated using the alkaline comet assay and genotyping was done using PCR-RFLP. The results revealed that the PONase activity toward paraoxonase and AChE activity was found significantly lowered in workers as compared to control subjects (p<0.001). Workers showed significantly higher DNA damage compared to control subjects (14.37±2.15 vs. 6.24±1.37 tail% DNA, p<0.001). Further, the workers with CYP2D6*3PM and PON1 (QQ and MM) genotypes were found to have significantly higher DNA damage when compared to other genotypes (p<0.05). In addition, significant increase in DNA damage was also observed in workers with concomitant presence of certain CYP2D6 and PON1 (Q192R and L55M) genotypes which need further extensive studies. In conclusion, the results indicate that the PON1 and CYP2D6 genotypes can modulate DNA damage elicited by some OPs possibly through gene-environment interactions.
authors: Division of Biochemistry & Biotechnology, National Centre for Disease Control 22, Sham Nath Marg, Delhi-110054, India.
authors: Satyender
authors: S
authors: Singh
authors: Vivek
authors: V
authors: Kumar
authors: Kapil
authors: K
authors: Vashisht
authors: Priyanka
authors: P
authors: Singh
authors: Basu Dev
authors: BD
authors: Banerjee
authors: Rajender Singh
authors: RS
authors: Rautela
authors: Shyam Sunder
authors: SS
authors: Grover
authors: Devendra Singh
authors: DS
authors: Rawat
authors: Syed Tazeen
authors: ST
authors: Pasha
authors: Sudhir Kumar
authors: SK
authors: Jain
authors: Arvind
authors: A
authors: Rai
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D043303:Aryldialkylphosphatase / Q000235:genetics*; D020552:Comet Assay; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D016273:Occupational Exposure; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010575:Pesticides / Q000633:toxicity*; D011110:Polymorphism, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D009943:Organophosphorus Compounds; D010575:Pesticides; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C510164:CYP3A5 protein, human; D019363:Cytochrome P-450 CYP1A1; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human