title: The role of PON1 and CYP2D6 genes in susceptibility to organophosphorus chronic intoxication in Egyptian patients.
abstract: BACKGROUND
  Paraoxonase-1 (PON1) activity toward organophosphorus(OP) compounds shows inter-individual variations, rendering the identification of individuals' PON1 allozymes valuable in treating patients suffering from organophosphorus intoxication. One of the most important cytochrome P450 monooxygenases (CYPs) is CYP2D6. The CYP2D6 G1934A polymorphism leads to good, poor or no enzyme activity. Genetic testing helps identification of high risk individuals as well as management of chronic intoxicated patients.
  
  
  OBJECTIVE
  to investigate a possible association between genetic polymorphisms of PON1 Q192R, and CYP2D6 G1934A as well as PON1 and pseudo-cholinesterase (PChE) enzyme activity levels and chronic organophosphate exposed patients, and hence, susceptibility for organophosphorus chronic poisoning.
  
  
  METHODS
  Thirty chronic organophosphate exposed farm workers were compared to 29 healthy controls as regards PON1 Q192R and CYP2D6 G1934A polymorphisms using PCR-RFLP technique. Also serum PON1 and PChE activities were determined spectrophotometrically.
  
  
  RESULTS
  Serum PChE was significantly reduced in chronic intoxicated patients compared to the control group (p=0.02), while PON1 activity was increased, but just failed to reach significance (p=0.06). PON1 192 RR genotype and R allele were significantly increased in chronic OP intoxicated patients (p=0.005 &p=0.002 respectively). CYP2D6 1934A allele was significantly increased in chronic OP patients (p=0.045). combining the two SNPs showed a significant statistical difference between the two groups with PON1QQ and CYP2D6 GG genotypes being more represented in the healthy controls (p=0.001). Fatigue and motor weakness were the most prevalent neurological symptoms seen in chronic cases (56.7%), followed by headache and lacrimation (30% each), depression (23%), tingling and sensory symptoms (20%), sleep disorders and limb pain (13%). The mean duration of environmental exposure to organophosphates was 7.7±5.2years and no association was found between chronic symptoms of intoxication and duration of exposure, provided that all workers were exposed for at least 3 years.
  
  
  CONCLUSIONS
  PON1 192RR genotype and CYP2D6 1934A allele were found to be related to the susceptibility to organophosphate chronic toxicity in Egyptians. Larger scale gene-environmental interaction studies are recommended to confirm results and Genotyping is recommended during selection of agricultural pesticide workers to exclude high risk group.
authors.affiliation: Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Cairo University, Kasr Al Aini street, Cairo, Egypt.
authors.forename: Amr Mohamed
authors.initials: AM
authors.lastname: Tawfik Khattab
authors.affiliation: Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Cairo University, Kasr Al Aini street, Cairo, Egypt.
authors.forename: Abeer Ahmed
authors.initials: AA
authors.lastname: Zayed
authors.affiliation: Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Kasr Al Aini street, Cairo, Egypt. Electronic address: asmaa.foraida@yahoo.com.
authors.forename: Asmaa Ismail
authors.initials: AI
authors.lastname: Ahmed
authors.affiliation: Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Cairo University, Kasr Al Aini street, Cairo, Egypt.
authors.forename: Aly Gamaleldin
authors.initials: AG
authors.lastname: AbdelAal
authors.affiliation: Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Cairo University, Kasr Al Aini street, Cairo, Egypt.
authors.forename: Alaa AbdelHamid
authors.initials: AA
authors.lastname: Mekdad
mesh_terms: D000328:Adult; D043303:Aryldialkylphosphatase / Q000235:genetics*; D016022:Case-Control Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004534:Egypt / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D062025:Organophosphate Poisoning / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D010755:Organophosphates / Q000633:toxicity; D010575:Pesticides / Q000633:toxicity; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D010755:Organophosphates; D010575:Pesticides; D019389:Cytochrome P-450 CYP2D6; D043303:Aryldialkylphosphatase
keywords: CYP2D6; Chronic intoxication; Organophosphates; PON-1