title: Paraoxonase and susceptibility to organophosphorus poisoning in farmers dipping sheep.
abstract: OBJECTIVE
  Human serum paraoxonase (PON1) hydrolyses organophosphate pesticides (OPs) entering the blood circulation and tissue fluid thus limiting toxicity. The PON1 coding region has two polymorphisms involving the amino acids at position 55 (Lt<--M) and 192 (Qt<--R), giving rise to isoenzymes which differ in their catalytic rate for the hydrolysis of OPs. We therefore hypothesized that individuals inheriting low activity isoforms of PON1 would be more liable to report symptoms of OP toxicity.
  
  
  METHODS
  We have therefore investigated the relationship between PON1 genetic polymorphisms and PON1 activity in farmers reporting chronic ill health which they attributed to OP exposure whilst sheep dipping (cases) and farmers who carried out similar activities, but remained well (controls). Diazoxon, paraoxon and phenylacetate were used as substrates for PON1. Diazoxon is the active metabolite of diazinon, the sheep dip most commonly used in the UK.
  
  
  RESULTS
  Cases were found to be more likely to have the R192 allele ( 0.01) and to have the L55 allele ( 0.05) than the controls. This combination of R and L genotypes was associated with lower PON1 activity towards diazoxon in both cases and controls. Farmers in the lowest quintile for the rate of serum diazoxon hydrolysis had a greater risk of being a case i.e. of reporting ill health (odds ratio 2.47 (95% CI 1.35-2.82)), than the other four quintiles of diazoxon hydrolysis. The rate of serum hydrolysis of paraoxon was greatest in cases and controls with the R/L haplotype (both 0.001).
  
  
  CONCLUSIONS
  The farmers reporting chronic ill health due to organophosphate exposure have a higher proportion of the PON1-192R polymorphism associated with lower rates of diazoxon hydrolysis and lower rates of diazoxon hydrolysis than the controls and that their ill health may be explained by a lower ability to detoxify diazoxon.
authors.affiliation: University Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. bmack@central.cmht.nwest.nhs.uk
authors.forename: Bharti
authors.initials: B
authors.lastname: Mackness
authors.forename: Paul
authors.initials: P
authors.lastname: Durrington
authors.forename: Andrew
authors.initials: A
authors.lastname: Povey
authors.forename: Stuart
authors.initials: S
authors.lastname: Thomson
authors.forename: Martin
authors.initials: M
authors.lastname: Dippnall
authors.forename: Mike
authors.initials: M
authors.lastname: Mackness
authors.forename: Ted
authors.initials: T
authors.lastname: Smith
authors.forename: Nicola
authors.initials: N
authors.lastname: Cherry
mesh_terms: D000818:Animals; D043303:Aryldialkylphosphatase; D015415:Biomarkers; D016022:Case-Control Studies; D004950:Esterases / Q000097:blood / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007306:Insecticides / Q000506:poisoning*; D008099:Liver / Q000201:enzymology; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D009784:Occupational Diseases / Q000201:enzymology / Q000235:genetics*; D062025:Organophosphate Poisoning; D009943:Organophosphorus Compounds; D010261:Paraoxon / Q000506:poisoning; D010648:Phenylacetates / Q000506:poisoning; D011110:Polymorphism, Genetic / Q000235:genetics*; D012307:Risk Factors; D012756:Sheep
chemical_list: D015415:Biomarkers; D007306:Insecticides; D009943:Organophosphorus Compounds; D010648:Phenylacetates; C000912:diazoxon; D004950:Esterases; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; C025136:phenylacetic acid; D010261:Paraoxon