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Considerations for Exposure to Diazinon and Chlorpyrifos - page 17 / 49





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PON1 Status

Recently, much better functional two-substrate assays have been developed that separate populations into individuals with specific functional genotypes as will be described below.  The assay also provides the level of enzyme present in the plasma of each individual.   An important genetic variability in the amino acid present at position 192 of this 355 amino acid protein [glutamine (Q) or arginine (R)] determines whether the PON1 in an individual can hydrolyze paraoxon rapidly or slowly.  Since the two so-called alloforms of paraoxonase (PON1-Q192 or PON1-R192) have different properties, this analysis provides the resolution of phenotypes shown in the slide.  In the data shown in this slide, DNA analysis was also carried out.  There were some discrepancies observed, where the DNA sequence was observed to specify a heterozygous genotype at position 192 (Q/R) where as the functional assay showed that only one alloform was present in the individual’s plasma.  Further studies involving sequencing the entire PON1 genes of these individuals elucidated the reason for the discrepancy.  These individuals had PON1 genes that were defective at regions of the gene away from that analyzed by the DNA analysis protocol as noted in the slide.  These observations serve to illustrate the accuracy of the functional 2-substrate assay.  

[Richter, RJ and Furlong, CE. 1999. Determination of paraoxonase (PON1) status requires more than genotyping.  Pharmacogenetics 9:745-753; Jarvik GP, R Jampsa, RJ Richter, C Carlson, M Rieder, D Nickerson and CE Furlong. 2003. Novel Paraoxonase (PON1) nonsense and missense mutations predicted by functional genomic assay of PON1 status. Pharmacogenetics 13:291-295.]

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