Superfund Research Program
PON1 as a Biomarker of Susceptibility to Environmentally-Induced Diseases
Paraoxonase (PON1), a liver and plasma enzyme that metabolizes oxidized lipids, was one of the first genes identified as environmentally relevant when it was determined that PON1 is an important determinant of sensitivity to organophosphate (OP) toxicity. Several polymorphisms in the PON1 gene have been described. Drs. Lucio Costa and Clement Furlong, SBRP-funded researchers at the University of Washington, are investigating various aspects of the functions and modulation of PON1 with the goal of increasing confidence in using it as a reliable biomarker of susceptibility for use in molecular epidemiology studies.
Drs. Costa and Furlong have studied PON1 polymorphisms extensively with respect to OP toxicity. They determined that a polymorphism of position 192 in the coding sequence of the gene significantly affects the catalytic efficiency of PON1, and that polymorphisms in the noncoding promoter region of the gene impact plasma levels of PON1 expression. Costa and Furlong determined that the polymorphism at position 192 results in substrate-specific alterations in the catalytic efficiency of PON1 as the PON1-R192 isoform results in increased catalytic efficiency with respect to paraoxon and the chlorpyrifos oxon, while the PON1-Q192 isoform hydrolyzes diazoxon, sarin, and soman more rapidly than PON1-R192. However, Costa and Furlong found that possessing efficient PON1 regulatory regions does not alone guarantee a high PON1 activity level. For example, they have shown that there is approximately a 15-fold variation in plasma levels of PON1 among PON1-Q192 individuals. This finding led them to propose the concept of determination of the "PON1 status" of an individual, which involves characterization of both the genotype (PON1-Q192 vs. PON1-R192) and the phenotype (level of PON1 in the plasma). They believe that determining both the PON1 genotype and plasma levels gives a more accurate measure of total PON1 activity, and is a critical step in studies of the association of PON1 and individual susceptibility to environmentally-induced diseases.
In collaboration with an SBRP-funded epidemiology study of Parkinson's Disease (see Research Brief 99), Costa and Furlong recently completed a study analyzing the associations between two PON1 coding region polymorphisms and two noncoding promoter regions in 150 Parkinson's Disease patients and 244 controls. Contrary to other reports, their results do not indicate that PD is associated with specific PON1 genotypes, suggesting that PON1 genotypes may not be predictive of Parkinson's Disease.
The researchers are currently conducting studies to examine the in vitro effects of the heavy metals aluminum (Al), cadmium (Cd), iron (Fe), lead (Pb), mercury (Hg), and zinc (Zn) on the activity of PON1. Cadmium, Fe, Zn and Hg appear to be the most potent inhibitors of PON1-R192, with concentrations as low as 100 nM causing greater than 80% inhibition. Overall, PON1-Q192 seems to be less sensitive to inhibition by metals. In the case of Fe, for example, 50 nM would cause 80% inhibition of PON1-R192, and only 20% inhibition of PON1-Q192. Lead was an exception in that it appeared to be more potent in inhibiting PON1-Q192 than PON1-R192.
PON1 polymorphisms play an important role in determining susceptibility to OP toxicity, and may impact susceptibility to atherosclerosis, cardiovascular disease, and other environmentally-induced diseases. These studies are providing a critical foundation for our understanding of the variables that must be considered when using PON1 as a biomarker of susceptibility in epidemiological studies.
For More Information Contact:
Lucio G Costa
University of Washington
Department of Environmental and Occupational Health Sciences
4225 Roosevelt Way NE, Suite 100
Seattle, Washington 98105
To learn more about this research, please refer to the following sources:
- Costa LG, Cole TB, Furlong CE. 2003. Polymorphisms of paraoxonse (PONl)and their significance in clinical toxicology of organophosphates. Toxicology 41(1):37-45. PMID:12645966
- Costa LG, Richter RJ, Li WE, Cole TB, Guizzetti M, Furlong CE. 2003. Paraoxonase (PON 1) as a biomarker of susceptibility for organophosphate toxicity. Biomarkers 8(1):1-12. doi:10.1080/13547500210148315 PMID:12519632
- Kelada SN, Costa-Mallen P, Checkoway H, Viernes HA, Farin FM, Costa LG, Longstreth WT, Furlong CE, Jarvik GP, Swanson PD. 2003. Paraoxonase 1 promoter and coding region polymorphisms in Parkinson's disease. Journal of Neurology, Neurosurgery & Psychiatry 74(4):546-547. PMID:12640090
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