The role of PON1 and CYP2D6 genes in susceptibility to organophosphorus chronic intoxication in Egyptian patients.
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.


DESIGN AND 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.


CONCLUSION
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.
['Tawfik Khattab|Amr Mohamed|AM|', 'Zayed|Abeer Ahmed|AA|', 'Ahmed|Asmaa Ismail|AI|', 'AbdelAal|Aly Gamaleldin|AG|', 'Mekdad|Alaa AbdelHamid|AA|']
D000328:Adult D043303:Aryldialkylphosphatase D016022:Case-Control Studies D019389:Cytochrome P-450 CYP2D6 D004534:Egypt D005260:Female D020022:Genetic Predisposition to Disease D005838:Genotype D006801:Humans D008297:Male D008875:Middle Aged D062025:Organophosphate Poisoning D010755:Organophosphates D010575:Pesticides D020641:Polymorphism, Single Nucleotide D012189:Retrospective Studies
CYP2D6 Chronic intoxication Organophosphates PON-1