Genetic and other sources of variation in the activity of serum paraoxonase/diazoxonase in humans: consequences for risk from exposure to diazinon.
Diazinon is the only organophosphorus insecticide that is currently approved for use in sheep dip in the UK. Reports that some individuals may be genetically more susceptible to possible chronic adverse health effects, due to variations in PON1 activity, are complicated by the reliability of activity measurements. In the present study, the influence of three polymorphisms of PON1 on serum diazoxonase activity was investigated in 85 healthy volunteers. Serum activity was assessed in as close to physiological conditions as possible (at pH 7.4, 150 mM NaCl and 37 degrees C with 50 microM diazoxon as substrate) and by quantifying pyrimidinol formation using high-performance liquid chromatography. PON1 genotypes were determined by the polymerase chain reaction and restriction enzyme digestion. For PON1 Q192R, individuals with the RR genotype had the highest serum diazoxonase activity, in contrast to some previous reports where activity was determined under less physiological conditions. Activity was slightly reduced in individuals with the QR genotype and activity was reduced even further in those with the QQ genotype. For PON1 L55 M, there was a significant decrease in mean enzyme activity from LL>LM>MM genotypes. The promoter polymorphism PON1 -108 C/T had only a slight effect on activity. Overall, intragenotype variation in PON1 activity was appreciably greater than the mean intergenotype differences. In conclusion, although there is a wide variation in activity in individuals both within and between genotypes, those individuals with a combination of Q and M alleles generally have a lower ability to detoxify diazoxon, which implies a potentially greater susceptibility to toxicity from diazinon.
O'Leary
Karen A
KA
Department of Health Toxicology Unit, Experimental Medicine and Toxicology, Imperial College London, Hammersmith Campus, London, UK.
Edwards
Robert J
RJ
Town
Margaret M
MM
Boobis
Alan R
AR
D000328:Adult; D000483:Alleles; D043303:Aryldialkylphosphatase / Q000097:blood* / Q000235:genetics*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003976:Diazinon / Q000494:pharmacology*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008956:Models, Chemical; D010597:Pharmacogenetics / Q000379:methods*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012306:Risk; D013696:Temperature; D013997:Time Factors
D002800:Cholinesterase Inhibitors; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D003976:Diazinon