Human PON1, a biomarker of risk of disease and exposure

doi:10.1016/j.cbi.2010.03.033

Chemico-Biological Interactions

Volume 187, Issues 1–3, 6 September 2010, Pages 355-361

https://doi.org/10.1016/j.cbi.2010.03.033 Get rights and content

Abstract

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 PON1₁₉₂ functional genotype and serum enzyme activity level, is required for a meaningful evaluation of PON1's 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.

Section snippets

Early studies

In 1953, Aldridge divided esterases into two categories, those that catalytically hydrolyzed organophosphate substrates (A-esterases) and those that were inhibited by organophosphates (B-esterases) [1]. Plasma paraoxonase 1 (PON1) is an A-esterase. Studies in the 1960s and 1970s demonstrated that PON1 activity was polymorphically distributed in human populations and the frequency of the low activity phenotype varied among populations of different ethnic origins. These studies are summarized in

Diseases associated with PON1 variability

In recent years, there have been approximately 500 papers published related to the association or lack of association of PON1 with specific diseases (PubMed searches). The largest number of studies has been carried out on vascular disease. Other diseases studied for their possible association with genetic variability in PON1 include Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), kidney disease, eye diseases, systemic lupus erythematosus, abdominal aortic aneurysms, asthma, chronic

PON1 status as a possible indicator of defects in the modulation of oxidative stress

Several recent studies have suggested linkage between Parkinson disease (PD) and genetic variability in the PON region of chromosome 7 [48], [49], [50], [51], while others have not [52], [53], [54], [55]. Based on our knowledge of the importance of PON1 status in risk of disease or exposure, we felt that it would be important to carry out a PON1 status analysis on a sizeable cohort of patients with PD. We expected to find lower PON1 levels in PD patients compared with control subjects as we had

PONs and quorum sensing

Ozer et al. reported that all three PONs hydrolyzed the quorum sensing factor of Pseudomonas aeruginosa N-(3-oxododecanoyl)-L- homoserine lactone (3OC12-HSL) [59]. Exposure experiments with PON1^−/− mice were inconclusive in demonstrating a protective effect for PON1 due to the abilities of PON2 and PON3 to inactivate 3OC12-HSL [59]. Experiments with PON2^−/− mice were more convincing with respect to demonstrating a protective role of PON2 against P. aeruginosa infection [60]. The ability of PON1

PON1 as a potential therapeutic

Our early studies [22], [23] following those of Main [20] indicated that it would be possible to use PON1 purified from human plasma to treat cases of CPF/CPO and DZ/DZO exposure, with the PON1_R192 alloform being the best choice of alloforms, since it hydrolyzes both CPO and DZO efficiently [24]. However, it will be necessary to engineer recombinant human PON1 for higher catalytic efficiency for use in treating exposure to OPs hydrolyzed with low catalytic efficiency [24], [62], [63].

To test

Immunolocalization of the PON family of enzymes

Circulating PON1 is synthesized in the liver [13], [68] and the secreted PON1 circulates in plasma tightly bound to HDL [68], using its unprocessed hydrophobic signal sequence as an anchor into the lipoprotein particles [13], [69]. Some authors have reported PON1 protein expression in kidney and aorta [70], [71]. Immunolocalization of PON1 has been described in nearly all the tissues of mice [72]. Specifically, PON1 was found in nearly all the studied epithelia, such as chondrocytes,

Summary

The many studies carried out on the PON family of enzymes have provided convincing evidence for the protective role of PON1 in modulating exposures to CPO/CPF and DZO/DZ, but not in modulating exposure to PS/PO or nerve agents. To protect against the latter OPs, PON1 will need to be engineered for increased catalytic efficiency. All three PONs appear to be important in modulating oxidative stress and protecting against vascular disease and perhaps other diseases that result from deficiencies in

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgements

This work was supported by the grants from the NIH (ES04696, ES09883; ES07033; ES09601, HL67406, R01 NS065070, P50 NS062684) and the Department of Veterans Affairs (Merit Review Award). JM was supported by a Beatriu de Pinós postdoctoral fellowship (2008 BP A 00166) from Comissionat per a Universitats i Recerca del Departament d’Innovació, Universitats i Empresa, Catalunya Spain.

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Mini reviewHuman PON1, a biomarker of risk of disease and exposure

Abstract

Section snippets

Early studies

Diseases associated with PON1 variability

PON1 status as a possible indicator of defects in the modulation of oxidative stress

PONs and quorum sensing

PON1 as a potential therapeutic

Immunolocalization of the PON family of enzymes

Summary

Conflict of interest

Acknowledgements

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Am. J. Hum. Genet.

Atherosclerosis

Toxicol. Appl. Pharmacol.

Arch. Biochem. Biophys.

Clin. Chim. Acta

Lancet

Toxicol. Appl. Pharmacol.

Lancet

J. Am. Coll. Cardiol.

J. Neurol. Sci.

Brain Res.

Neurosci. Lett.

Genet. Med.

Biochim. Biophys. Acta

FEMS Microbiol. Lett.

Toxicology

Anal. Biochem.

Chem. Biol. Interact.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Free Radic. Biol. Med.

Two types of esterase (A and B) hydrolysing p-nitrophenyl acetate, propionate and butyrate, and a method for their determination

Biochem. J.

The human serum paraoxonase-polymorphism and specificity

Toxicol. Environ. Chem.

Paraoxon hydrolysis in human serum mediated by a genetically variable arylesterase and albumin

Am. J. Hum. Genet.

The human serum paraoxonase/arylesterase polymorphism

Am. J. Hum. Genet.

Determination of paraoxonase (PON1) status requires more than genotyping

Pharmacogenetics

The molecular basis of the human serum paraoxonase activity polymorphism

Nat. Genet.

Molecular basis for the polymorphic forms of human serum paraoxonase/arylesterase: glutamine or arginine at position 191, for the respective A or B allozymes

Am. J. Hum. Genet.

The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin

Nat. Genet.

Determination of paraoxonase 1 status without the use of toxic organophosphate substrates

Circ. Cardiovasc. Genet.

PON1 status of farmworker mothers and children as a predictor of organophosphate sensitivity

Pharmacogenet. Genomics

Characterization of cDNA clones encoding rabbit and human serum paraoxonase: the mature protein retains its signal sequence

Biochemistry

Promoter polymorphisms of human paraoxonase PON1 gene and serum paraoxonase activities and concentrations

Arterioscler. Thromb. Vasc. Biol.

Paraoxonase-1 promoter haplotypes and serum paraoxonase: a predominant role for polymorphic position—107, implicating the Sp1 transcription factor

Biochem. J.

Mini review
Human PON1, a biomarker of risk of disease and exposure