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Paraoxonase (PON1): from Toxicology to Cardiovascular Medicine Lucio G

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Paraoxonase (PON1): from Toxicology to Cardiovascular Medicine Lucio G costa 28-09-2005 14:09 Pagina 50 ACTA BIOMED 2005; Suppl 2; 50-57 © Mattioli 1885 C ONFERENCE R EPORT Paraoxonase (PON1): from toxicology to cardiovascular medicine Lucio G. Costa1,2, Toby B. Cole2, 3, Clement E. Furlong3 1Dept of Human Anatomy, Pharmacology and Forensic Science, University of Parma Medical School, Parma, Italy; 2Dept. of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; 3Depts. of Medicine (Div. Med.Genetics) and Genome Sciences, University of Washington, Seattle, WA, USA Abstract. Paraoxonase (PON1) is a liver and plasma enzyme most studied because of its ability to hydrolyze the active metabolites of several organophosphorus insecticides. The discovery that PON1 can also metabo- lize oxidized phospholipids has spurred research on its possible role in coronary heart disease and atheroscle- rosis. Additionally, its potential roles in metabolizing pharmaceutical drugs and microbial quorum sensing fac- tors are also being explored. PON1 displays several polymorphisms that influence both its level of expression and its catalytic activity, thus determining the rates at which a given individual will detoxify a specific insecti- cide, metabolize harmful oxidized lipids, and activate or inactivate specific drugs and quorum sensing factors. Key words: Paraoxonase (PON1) polymorphisms, organophosphates, PON1 status, coronary artery disease, drug metabolism, quorum sensing factors Introduction PON1 and its human polymorphisms Paraoxonase (PON1) received its name from PON1 is a member of a family of proteins that paraoxon, the active metabolite of the organophospho- also includes PON2 and PON3, the genes of which rus (OP) insecticide parathion, which is its first and are clustered in tandem on the long arm of human one of its most studied substrates. As PON1 hy- chromosome 7 (q21.22). PON1 is synthesized pri- drolyzes the active metabolites of several other OPs marily in the liver and a portion is secreted into the (e.g. chlorpyrifos oxon, diazoxon), as well as nerve plasma, where it is associated with high density agents such as soman, sarin or VX, it has been studied lipoprotein (HDL) particles (1-3). mostly by toxicologists, interested in its role in modu- Earlier studies had indicated that the plasma lating OP toxicity. Yet the discovery that PON1 can paraoxonase activity in human populations exhibited a metabolize oxidized lipids (LDL and HDL) has polymorphic distribution, and individuals with low, spurred an extensive series of investigations on the po- intermediate or high paraoxonase activity could be tential role of PON1 in cardiovascular disease, partic- identified (4, 5). Studies in the early 1990s led to the ularly in atherosclerosis. Furthermore, the finding that purification, cloning and sequencing of human PON1 PON1 and the related proteins PON2 and PON3 dis- (6, 7), and to the molecular characterization of its play lactonase activity, has provided evidence that they polymorphisms (8, 9). More recently, the molecular may be involved in drug metabolism and inactivation structure of an engineered recombinant PON1 pro- of quorum sensing factors as well. As a result, research tein has also been elucidated (10). Two polymor- in these fields has blended, with the goal of further elu- phisms are present in the PON1 coding sequence: a cidating the role of this polymorphic enzyme in disease Gln(Q)/Arg(R) substitution at position 192, and a and in an individual’s response to exogenous agents. Leu(L)/Met(M) substitution at position 55 (8, 9). costa 28-09-2005 14:09 Pagina 51 Paraoxonase in toxicology and medicine 51 The Q/R polymorphism at position 192 significantly zyme levels or catalytic efficiencies, has suggested that affects the catalytic efficiency of PON1. Initial studies certain individuals may be more susceptible to the tox- demonstrated that the PON1R192 allozyme hydrolyzes ic effects of OP exposure. Over the past 15 years, a se- paraoxon more readily than PON1Q192 (8, 9). Further ries of studies in rodents has provided important evi- studies showed that this polymorphism was substrate- dence to ascertain the role of PON1 in modulating dependent, as the PON1 Q192 alloform was found to OP toxicity. In earlier studies, PON1 purified from hydrolyze diazoxon, sarin and soman more rapidly rabbit serum was injected into rats or mice to increase than PON1 R192 in vitro (11). More recent studies, plasma hydrolytic activity toward OP substrates. however, have shown that under physiological condi- When challenged with an OP (chlorpyrifos oxon was tions, both PON1 alloforms hydrolyze diazoxon with used in most instances), animals which had received nearly equivalent catalytic efficiencies (12). Gene fre- exogenous PON1 were significantly more resistant quencies of PON1 Q192 range from 0.75 for Caucasians than controls to the acute cholinergic toxicity (19-21). of Northern European origin, to 0.31 for some Asian Of interest is that PON1 provided some protection populations (13). against chlorpyrifos, the parent compound that is used The L/M polymorphism at position 55 does not as insecticide, when given before or even after this OP affect catalytic activity, but has been associated with (21). plasma PON1 protein levels, with PON1M55 being as- More recently, transgenic and knockout mice sociated with low plasma PON1 (14, 15). However, have provided important new tools to investigate the this appears to result primarily from linkage disequi- role of PON1 in modulating OP toxicity. PON1 librium with the low efficiency –108T allele of the T- knockout mice, which have no detectable plasma or 108C promoter region polymorphism (13). Four addi- liver hydrolytic activity toward paraoxon and diazoxon tional polymorphisms have been found in the 5’-reg- and very limited chlorpyrifos-oxonase activity, have ulatory region of PON1 (16), but they have a lesser ef- dramatically increased sensitivity to the toxicity of fect on PON1 protein level (17). Recent complete re- chlorpyrifos oxon and diazoxon, and a small increase sequencing of PON1 from several individuals has led in sensitivity to their respective parent compounds to the identification of nearly 200 new single nu- (12, 22). Surprisingly, they did not show an increased cleotide polymorphisms, some in the coding regions sensitivity to paraoxon (12). and others in introns and regulatory regions of the Administration of pure human PON1Q192 or gene (18; http://pga.gs.washington.edu). Though PON1R192 to PON1 knockout mice to restore plasma most of the new polymorphisms have not yet been PON1 provided additional important information. characterized, a few have already explained discrepan- PON1R192 provided better protection than PON1 Q192 cies found when comparing PON1 status and PCR toward chlorpyrifos oxon, while both alloforms were analysis of codon 192 [see below; (18)]. equally effective in protecting against the toxicity of diazoxon (12). However, neither PONR192 nor PON1Q192 afforded protection against paraoxon toxic- PON1 and its role in organophosphate toxicity ity (12). A kinetic analysis of substrate hydrolysis by purified human alloforms carried out under physio- PON1 hydrolyzes the oxygen analogs of several logical conditions (low NaCl concentration) provided OPs; however, it does not hydrolyze directly the par- an explanation for the in vivo findings. In the case of ent compound of such insecticides (i.e. parathion, chlorpyrifos oxon, the PON1R192 alloform had signifi- chlorpyrifos, diazinon), nor several other OPs (e.g. cantly higher catalytic efficiency (250 vs. 150) than malaxon, guthion, dichlorvos) (3). Nevertheless, the the PON1Q192 alloform and provided better protection ability of PON1 to hydrolyze several OPs in vitro has against CPO exposure. In the case of diazoxon, both long been taken as an indication that it may modulate PON1Q192R alloforms had equivalent catalytic efficien- OP toxicity in vivo. Furthermore, the presence of cies (~76) and provided equivalent protection. With polymorphisms in PON1, which confer different en- paraoxon, the PON1R192 alloform was much more effi- costa 28-09-2005 14:09 Pagina 52 52 L.G. Costa, T.B. Cole, C.E. Furlong cient than the PON1Q192 alloform (6 vs. 0.7) with in the plasma level of PON1 for each individual, thus vitro assays, but its overall catalytic efficiency was very encompassing the two factors that affect PON1 levels low and unable to confer protection in vivo (12). This or activity. For example, sensitivity to diazoxon expo- confirmed the hypothesis that PON1 is not efficient sure (12) or risk of carotid artery disease (27) is influ- at hydrolyzing paraoxon at low concentrations (23), enced primarily by PON1 levels, which are not as- indicating that human and mouse PON1s do not de- sessed by PCR-based assays. The catalytic efficiency grade paraoxon efficiently in vivo. Additional experi- with which PON1 degrades toxic OPs determines the ments carried out in PON1 transgenic mice (mice ex- degree of protection provided by PON1; in addition, pressing either human PON1Q192 or PON1R192 on a higher concentrations of PON1 provide better pro- knockout background) provided further evidence for tection. Thus, it is important to know PON1 levels the conclusions made from experiments administrat- and activity. This approach has been referred to as the ing PON1 to PON1 knockout mice. For example, determination of PON1 “status” for an individual hPON1R192-TG mice were significantly less sensitive (25). In a given population, plasma PON1 activity can to the toxicity of chlorpyrifos
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