The paraoxonases: role in human diseases and methodological difficulties in measurement

Abstract

Research into the paraoxonase (PON) gene family has flourished over the past few years. In the 1970s and 1980s, only PON1 was known, and the investigations were conducted, essentially, by toxicologists focusing on protection against organophosphate poisoning. Since then, two new members of the family, PON2 and PON3, have been identified, both being shown to play antioxidant and anti-inflammatory roles. Evidence exists indicating that the PON family is central to a wide variety of human illnesses such as cardiovascular disease, diabetes mellitus, metabolic syndrome, obesity, non-alcoholic steatohepatitis, and several mental disorders. However, research is hampered considerably by the methods currently available to measure the activity of these enzymes. In this review, we summarize the state of knowledge on PON biochemistry and function, the influence of genetic variations, and the involvement of PON in several diseases. The problems associated with PON measurement, such as sample acquisition, lack of reference methods, and variety of substrates, will be presented. Also, we cover some of the present lines of research and propose some others for future progress in this field.

Paraoxonase-1 status in patients with hereditary hemochromatosis

“…Conversely, low PON1 levels are associated with an enhanced sensitivity to liver disease ( 17 ). PON1 levels are genetically determined; the polymorphisms Arg/Gln at position 192 ( PON1 192 , with two alleles termed Q and R) and Leu/Met at position 55 ( PON1 55 , with two alleles termed L and M), are strongly associated with the enzyme's activity ( 9 ). PON1 55 polymorphism indirectly infl uences serum PON1 activity and concentration; i.e., it is in linkage disequilibrium with the PON1 -108 promoter polymorphism, the mutation really responsible for the observed changes ( 18 ).…”

Evidence for association between paraoxonase 1 gene polymorphisms and polycystic ovarian syndrome in south-west Chinese women

“…Serum paraoxonase 1 (PON1) is a calcium-dependent esterase/lactonase, which is and mainly synthesized by the liver and circulates within HDL particles (11,12). PON1 has PON, arylesterase, and lactonase activities (11).…”

“…PON1 has PON, arylesterase, and lactonase activities (11). The enzyme not only hydrolyzes several organophosphorus insecticides and nerve agents, which is involved in the protection against xenobiotic toxicity (12), but also inhibits LDL oxidation, increases macrophage-associated cholesterol efflux, and possesses antioxidant, anti-inflammatory, and anti-atherogenic properties (11,13).…”

“…The 192Q/R (rs662) polymorphism has been shown to affect PON1 activities in a substrate-dependent manner such that paraoxon (14,15,16) is hydrolyzed in vitro more efficiently by the R isoform, whereas diazoxon, soman, sarin (15), and lipid peroxides (11,12,17) are hydrolyzed more rapidly by the Q isoform, but there are contradictory data about the relationship between 192 isoforms and the rates of phenylacetate hydrolysis (14,15,18). Both the PON1 55L/M (rs854560) and the PON1 K108C/T (rs705379) variants are associated with variations in concentrations (11,12,18). As genetic factors, including polymorphism, were found to explain more than 60% phenotypic variance in PON1 activity (14), PON1 genetic factors may have an important effect on the physiological function of PON1 and its association with diseases.…”

“…As genetic factors, including polymorphism, were found to explain more than 60% phenotypic variance in PON1 activity (14), PON1 genetic factors may have an important effect on the physiological function of PON1 and its association with diseases. Studies showed that some of the PON1 polymorphisms were associated with several disorders: the PON1 192Q/R polymorphism was associated with coronary heart disease (19,20), ischemic stroke (21), Alzheimer's disease (11), and chronic kidney disease (22); the PON1 55L/M polymorphism was associated with Parkinson's disease (23); and the PON1 K108C/T polymorphism was associated with increased serum glucose concentrations in nondiabetic patients (24).…”