The Paraoxonases: Their Role in Disease Development and Xenobiotic Metabolism

Volume 6 of the series Proteins And Cell Regulation pp 267-281

The Functional Consequences of Polymorphisms in the Human PON1 Gene

  • C.E. FurlongAffiliated withDepartments of Medicine (Div. Medical Genetics)Genome Sciences
  • , R.J RichterAffiliated withDepartments of Medicine (Div. Medical Genetics)Genome Sciences
  • , W.-F. LiAffiliated withDivision of Environmental Health and Occupational Medicine, National Health Research Institutes
  • , V.H. BrophyAffiliated withDepartments of Medicine (Div. Medical Genetics)Genome SciencesRoche Diagnostics
  • , C. CarlsonAffiliated withGenome SciencesThe Fred Hutchinson Cancer Research Center
  • , M. RiederAffiliated withGenome Sciences
  • , D. NickersonAffiliated withGenome Sciences
  • , L.G. CostaAffiliated withEnvironmental and Occupational Health Sciences, University of WashingtonDept. of Human Anatomy Pharmacology and Forensic Medicine, University of Parma
  • , J. RanchalisAffiliated withDepartments of Medicine (Div. Medical Genetics)Genome Sciences
    • , A.J. LusisAffiliated withDepartment of Medicine, UCLA
    • , D.M. ShihAffiliated withDepartment of Medicine, UCLA
    • , A. TwardAffiliated withDepartment of Medicine, UCLAUniversity of California
    • , G.P. JarvikAffiliated withDepartments of Medicine (Div. Medical Genetics)Genome Sciences

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Early research on population distributions of plasma PON1 paraoxonase activity indicated a polymorphic distribution with high, intermediate and low metabolizers. Cloning and characterization of the cDNA encoding human PON1 and follow-on experiments demonstrated that the molecular basis of the activity polymorphism (PM) was a Q192R PM with PON1R192 specifying high paraoxonase activity. Further research demonstrated that the PON1192 polymorphism had little effect on the catalytic efficiencies of hydrolysis of phenylacetate and diazoxon (DZO), but did affect the efficiencies of hydrolysis of chlorpyrifos oxon (CPO), soman and sarin, with PON1R192 having a higher efficiency of CPO hydrolysis and PON1Q192 having higher rates of hydrolysis of soman and sarin. Plots of rates of DZO hydrolysis (at a salt concentration that differentially inhibited PON1R192) vs. paraoxon hydrolysis clearly separated the three PON1192 phenotypes (QQ, QR, RR) and also showed a wide range of activity among individuals with the same PON1192 genotype. The term PON1 status was introduced to include both PON1192 functional genotype and plasma PON1 level,both important in determining risk for either exposure to specific organophosphorus compounds (OPs) or disease. Characterization of 5 promoter-region polymorphisms by several groups indicated that an Sp1 binding site was responsible for significant(~30%) variation in plasma PON1 levels. Re-sequencing of the PON1 genes of 47 individuals (24 African-American/23 European) revealed an additional 180 polymorphisms in 27 kb of the PON1 genomic DNA including 8 more 5' regulatory region PMs, 1 coding region polymorphism (W194X), 162 additional intronic PMs and 9 additional 3' UTR PMs. The generation of PON1 null mice and “PON1 humanized mice” expressing either tgHuPON1R192 or tgHuPON1Q192 at the same levels on the PON1−/− background allowed for a functional analysis of the Q192R PM under physiological conditions. Toxicology experiments with the PON1 humanized mice and the PON1 null mice injected with purified human PON1192 alloforms clearly demonstrated that the catalytic efficiency of substrate hydrolysis is important in determining whether PON1 is able to protect against a given OP exposure. HuPON1R192 protects well against CPO and DZO exposure, but HuPON1Q192 does not protect well against CPO exposure and neither protects against PO exposure. Studies on PON1 status and carotid artery disease show that low PON1 levels are a risk factor. The effects of PON1192 alloforms on rates of hydrolysis of quorum sensing factors are not yet known. Taken together, these data along with those of the leading researchers in the PON1 field indicate that it is important to measure PON1 levels/activities in any epidemiological study. SNP analysis alone is inadequate for epidemiological studies, due to the wide variability of PON1 levels within the three PON1192 genotypes Q/Q, Q/R R/R). Even the most comprehensive PON1 SNP analyses are unable to accurately predict PON1 levels. PON1 activity or level accurately predicts CHD risk, while genotype does not


paraoxonase PON1 organophosphate organophosphorus compounds (OPs) chlorpyrifos chlorpyrifos oxon diazinon diazoxon arylesterase regulation of gene expression nerve agents single nucleotide polymorphisms (SNPs) PON1 expression Sp1 transcription factor quorum sensing quorum sensing factor carotid artery disease (CAAD) coronary heart disease (CHD)