R. J. Richter
University of Washington
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Chemico-Biological Interactions | 2010
Clement E. Furlong; Stephanie M. Suzuki; R.C. Stevens; Judit Marsillach; R. J. Richter; Gail P. Jarvik; Harvey Checkoway; A. Samii; L. G. Costa; A. Griffith; J.W. Roberts; D. Yearout; C.P. Zabetian
Human paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated serum enzyme that exhibits a broad substrate specificity. In addition to protecting against exposure to some organophosphorus (OP) pesticides by hydrolyzing their toxic oxon metabolites, PON1 is important in protecting against vascular disease by metabolizing oxidized lipids. Recently, PON1 has also been shown to play a role in inactivating the quorum sensing factor N-(3-oxododecanoyl)-l-homoserine lactone (3OC12-HSL) of Pseudomonas aeruginosa. Native, untagged engineered recombinant human PON1 (rHuPON1) expressed in Escherichia coli and purified by conventional column chromatographic purification is stable, active, and capable of protecting PON1 knockout mice (PON1(-/-)) from exposure to high levels of the OP compound diazoxon. The bacterially derived rHuPON1 can be produced in large quantities and lacks the glycosylation of eukaryotic systems that can produce immunogenic complications when inappropriately glycosylated recombinant proteins are used as therapeutics. Previous studies have shown that the determination of PON1 status, which reveals both PON1(192) functional genotype and serum enzyme activity level, is required for a meaningful evaluation of PON1s role in risk of disease or exposure. We have developed a new two-substrate assay/analysis protocol that provides PON1 status without use of toxic OP substrates, allowing for use of this protocol in non-specialized laboratories. Factors were also determined for inter-converting rates of hydrolysis of different substrates. PON1 status also plays an important role in revealing changes in HDL-associated PON1 activities in male patients with Parkinson disease (PD). Immunolocalization studies of PONs 1, 2 and 3 in nearly all mouse tissues suggest that the functions of PONs 1 and 3 extend beyond the plasma and the HDL particle.
Archive | 1987
Lucio G. Costa; R. J. Richter; Sheldon D. Murphy; Gilbert S. Omenn; Arno G. Motulsky; Clement E. Furlong
Paraoxon (diethyl-p-nitrophenylphosphate) is the active metabolite of parathion (diethyl-p-nitrophenylphosphorothioate), a widely used organo-phosphorus insecticide. After activation of parathion by the cytochrome P450 system, the paraoxon is hydrolyzed by a serum enzyme, paraoxonase (EC 3.1.1.2), to generate p-nitrophenol and diethylphosphoric acid (Zech and Zurcher, 1974). Measurement of paraoxonase activity in sera from human subjects of European origin (i.e. Caucasian) has revealed a bimodal or trimodal distribution (Mueller et al. 1983; Eckerson et al. 1983). Cn the basis of enzymatic tests, humans can be divided into three serum paraoxonase phenotypes: A (low activity), AB (intermediate activity), and B (high activity), with about 50% of the studied populations of European origin displaying low activity (Eckerson et al. 1983).
Human and Ecological Risk Assessment | 2002
Clement E. Furlong; Wf Li; Diana M. Shih; Aldons J. Lusis; R. J. Richter; L. G. Costa
In mammals, serum paraoxonase (PON1) is tightly associated with high-density lipoprotein (HDL) particles. In human populations, PON1 exhibits a substrate dependent activity polymorphism determined by an Arg/Gln (R/Q) substitution at amino acid residue 192. The physiological role of this protein appears to be involvement in the metabolism of oxidized lipids. Several studies have suggested that the PON1R192 allele may be a risk factor in coronary artery disease. PON1 also plays an important role in the metabolism of organophosphates including insecticides and nerve agents. The PON1R192 isoform hydrolyzes paraoxon rapidly, but diazoxon, soman and sarin slowly compared with the PON1Q192 isoform. Both PON1 isoforms hydrolyze phenylacetate at approximately the same rate, while PON1R192 hydrolyzes chlorpyrifos oxon slightly faster than PONQ192. Animal model studies involving injection of purified rabbit PON1 into mice clearly demonstrated the ability of PON1 to protect cholinesterases from inhibition by OP compounds. The consequence of having low PON1 levels has been addressed with toxicology studies in PON1 knockout mice. These mice showed dramatically increased sensitivity to chlorpyrifos oxon, diazoxon and some increased sensitivity to the respective parent compounds. These observations are consistent with earlier studies that showed a good correlation between high rates of OP hydrolysis by serum PON1 and resistance to specific OP compounds. They are also consistent with the observations that newborns have an increased sensitivity to OP toxicity, due in part to their not expressing adult PON1 levels for weeks to months after birth, depending on the species. Together, these studies point out the importance of considering the genetic variability of PON1192 isoforms and levels as well as the developmental time course of PON1 appearance in serum in developing risk assessment models
American Journal of Human Genetics | 1988
Clement E. Furlong; R. J. Richter; S L Seidel; Arno G. Motulsky
Chemico-Biological Interactions | 1999
L. G. Costa; Wf Li; R. J. Richter; Diana M. Shih; Aldons J. Lusis; Clement E. Furlong
Neurotoxicology | 2000
Clement E. Furlong; Wf Li; R. J. Richter; Diana M. Shih; Aldons J. Lusis; E. Alleva; L. G. Costa
American Journal of Human Genetics | 1984
J Ortigoza-Ferado; R. J. Richter; S K Hornung; Arno G. Motulsky; Clement E. Furlong
Archive | 2000
Wf Li; L. G. Costa; R. J. Richter; Terje P. Hagen; Dm Shih; Aaron D. Tward; Aldons J. Lusis; Clement E. Furlong
Neurotoxicology | 2000
Clement E. Furlong; Wf Li; Victoria H. Brophy; Gail P. Jarvik; R. J. Richter; Diana M. Shih; A. J. Lusis; L. G. Costa
Neurotoxicology | 1998
Clement E. Furlong; Wf Li; L. G. Costa; R. J. Richter; Diana M. Shih; A. J. Lusis