Paraoxonase 1 (PON1) Status in Risk Assessment for

Chapter 9

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Paraoxonase 1 (PON1) Status in Risk Assessment for Organophosphate Exposure and Pharmacokinetics Clement E. Furlong,*,1 Rebecca J. Richter,1 Lucio G. Costa,2 and Gail P. Jarvik1 1Departments of Medicine (Division of Medical Genetics) and Genome Sciences, University of Washington, Seattle, Washington 98195 2Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195 *E-mail: [email protected]

The use of enzymatic rate constants for physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling requires that the rate constants are physiologically relevant. To illustrate some of the approaches used to establish the validity and physiologically significance of in vitro determined rate constants, we have made use of data for the human high density lipoprotein (HDL)-associated enzyme paraoxonase 1 (PON1) and a mouse model system in which the PON1 protein levels and catalytic efficiency are genetically variable. A glutamine (Q)/arginine (R) polymorphism at amino acid position 192 of PON1 (Q192R) determines the catalytic efficiency of hydrolysis of some substrates with the PON1R192 alloform, for example, hydrolyzing chlorpyrifos oxon (CPO) more efficiently than the PON1Q192 alloform and protecting better against CPO exposure. The PON1-Q192R alloforms have equivalent catalytic efficiencies of diazoxon (DZO) hydrolysis and protect equally well against DZO exposure. The catalytic efficiency for paraoxon (PO) hydrolysis is too low to effectively protect against PO exposure. Epidemiological studies on human

© 2012 American Chemical Society In Parameters for Pesticide QSAR and PBPK/PD Models for Human Risk Assessment; Knaak, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


populations have shown that low PON1 levels are also a risk factor for vascular disease. Km values for substrate hydrolysis are presented as well as tables for interconverting rates of hydrolysis of different substrates to allow modeling of in vivo rates of OP substrate hydrolysis at different in vivo levels of OP when rates of hydrolysis of a non-toxic substrate such as phenyl acetate are measured in vitro. Establishment of correlation plots for drug metabolism will allow for the conversion of difficult assays to convenient high-throughput assays.

Introduction The high density lipoprotein (HDL)-associated esterase/lactonase paraoxonase 1 (PON1) provides a good example for determining relevant catalytic rates and rate constants for physiologically based pharmacokinetic/ pharmacodynamic (PBPK/PD) modeling. PON1 is the primary enzyme responsible for the in vivo inactivation of the toxic oxon forms of the organophosphorus (OP) insecticides chlorpyrifos (CPS) and diazinon (DZS) that are either generated in the environment (1–3) or in vivo by cytochrome P450 bioactivation of the parent organophosphorothioate compounds (4) (Figure 1). Most of the early studies on PON1 were associated with its role in the metabolism of organophosphorus insecticides [reviewed in (5)]. Other reviews provide overviews of the more recent research on PON1 (6, 7). The observation by Mackness and coworkers that PON1 was the protein in HDL that prevented oxidation of LDL (8) led to an avalanche of papers examining the possible relationship between PON1 genetic variability and risk of cardiovascular disease [reviewed in (9)]. Unfortunately, most of the studies examining the relationship of PON1 genetic variability to vascular disease characterized only the DNA polymorphism(s) and did not examine plasma PON1 activity levels, the most important parameter to measure for risks of disease or exposures – it is after all, the rate of catalysis that determines the rate of detoxication of xenobiotics or physiological toxins and in turn, the risk of exposure or disease. Studies that did include measures of plasma PON1 activity levels within a PON1192 genotype or with a substrate such as phenyl acetate (10), the hydrolysis of which was not affected by the Q192R polymorphism, did observe an association of low PON1 activity levels with risk of vascular disease (e.g., (11, 12)). The importance of determining PON1 activity levels in epidemiological studies has been pointed out by researchers with the most experience in PON1 physiology (9, 11, 13, 14). These studies are mentioned here since modeling of metabolism should also consider rates of metabolism of endogenous substrates (e.g., oxidized lipids), especially those that are risk factors for disease. The physiological substrates for PON1 are yet to be fully elaborated, however, it is clear from the studies done to date that plasma PON1 activity level is important for determining risk of vascular disease. 134 In Parameters for Pesticide QSAR and PBPK/PD Models for Human Risk Assessment; Knaak, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Figure 1. Compounds discussed in this chapter.

More recent research has elucidated the role of PON1 in the metabolism of drugs with PON1 bioactivating some such as prulifloxacin (15) and inactivating others including glucocorticoid gamma-lactones and cyclic carbonates (16). The proposal that PON1 plays an important role in bioactivating clopidogrel (17) remains a disputed question (18, 19). Another important physiological substrate of PON1, the quorum sensing factor of Pseudomonas aeruginosa, was the most recently described function of PON1 (20). Generation of a transgenic Drosophila that expressed PON1 resulted in a transgenic fly that was resistant to the pathogenesis of a Pseudomonad infection as well as exposure to chlorpyrifos (21). These experiments have implicated PON1 in the innate immune system. 135 In Parameters for Pesticide QSAR and PBPK/PD Models for Human Risk Assessment; Knaak, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

Thus, there are many physiological functions for which the pharmaco-kinetics and genetic variability of PON1 are important. Since most is known about the genetic variability of PON1 and resistance to OP exposures, this review will focus on the pharmacokinetic characterization of PON1 and OP compounds with approaches described for developing protocols for establishing in vivo rates of metabolism of other physiological relevant molecules including drugs.

Development of Animal Models


Studies with Wild Type Rodents The role of human paraoxonase 1 (PON1) in protecting against exposures to specific organophosphorus (OP) insecticides has been studied for more than half a century. Early studies showed a correlation between plasma PON1 levels and resistance to specific OPs [reviewed in (7)]. Validation of these observations was established by experiments where purified PON1 was injected into rodents (22, 23). The first experiments involved the injection of purified rabbit PON1 (which has very high activity) into rats. The injected PON1 provided some protection against paraoxon (PO) exposure (22, 23) but better protection against exposure to chlorpyrifos oxon (23). Following these early experiments, mice were chosen as an improved animal model, since they were much smaller and required much less purified PON1 for each injection experiment and it was also clear that it was much easier to generate genetically-modified strains of mice (24). The initial experiments with mice involved injection of purified rabbit PON1 into wild type mice (24, 25). These experiments provided clear evidence that high levels of plasma PON1 provided excellent protection against CPO exposure as well as some protection against exposure to the parent organophosphorothioate chlorpyrifos.

Development of the PON1 Knockout Mouse (PON1-/-) The generation of PON1-/- mice by Drs. Shih and Lusis at UCLA (26) allowed for the examination of the effects of low levels of PON1 on sensitivity to OP exposures and vascular disease and also provided a platform for examining the physiological function of engineered PON1 variants when injected into the PON1-/- mice (27). Further experiments demonstrated that PON1 provided good protection against exposures to the oxon forms of chlorpyrifos and diazinon, but protected less well against exposures to the respective parent compounds (28). However, it was surprising that the PON1 null mice were not more sensitive than wild type mice to exposures of PO, the compound from which PON1 received its name. The use of PON1-/- mice in modeling experiments was demonstrated by Cole et al. (29). The PON1 null mice also allowed for the injection of purified PON1Q192 and PON1R192 alloforms. The degree of protection against chlorpryifos oxon and diazoxon correlated well with the respective catalytic efficiency for hydrolysis of each oxon. In agreement with the lack of increased sensitivity of the PON1 136 In Parameters for Pesticide QSAR and PBPK/PD Models for Human Risk Assessment; Knaak, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


null mice to paraoxon, injection of neither PON1192 alloform protected against paraoxon exposure (28). Despite the fact that the catalytic efficiency for the hydrolysis of PO by PON1R192 was nine-times as efficient as hydrolysis by PON1Q192, the catalytic efficiency was still too low to protect against PO exposure. The experiments involving the injection of purified PON1 into PON1-/- mice provided important insights into the importance of catalytic efficiency of catalysis in determining the physiological significance of a given enzyme for a specific catalytic function. The PON1 null mouse also provided an ideal model system for testing the efficacy of recombinant human PON1 variants proteins to protect against OP exposures since diazoxonase activity is not detectable in the serum of the PON1-/mouse, making the half-life and persistence of injected PON1 easy to determine. The high activity PON1K192 variant when injected into PON1-/- mice protected against 2-3 LD50 dermal doses of diazoxon (27).

PON1 Status In 1993, we introduced the term PON1 status to encompass the functional position 192 genotype of PON1 as well as plasma activity levels (24). In 1996 we reported that a two-substrate/two-dimensional analysis of plasma PON1 hydrolytic activity provided a clear resolution of the functional position 192 genotype as well as plasma PON1 activity (30). Plotting rates of diazoxon hydrolysis against rates of paraoxon hydrolysis clearly separated the three PON1192 phenotypes, PON1192Q/Q; PON1192Q/R and PON1192R/R (30). Recently we reported that it was possible to use safer, non-OP substrates to determine PON1 status (31, 32). Figure 2 shows a comparison of the earlier two-substrate analysis using diazoxon and paraoxon as the substrate pair with an analysis using hydrolysis of phenyl acetate at high salt and 4-chloromethylphenyl acetate at low salt as the non-OP substrate pair. The following approach is useful for characterizing rates of reaction of plasma enzymes. To develop kinetic parameters for use in PBPK/PD modeling, we carried out kinetic analyses under physiological conditions of salt and pH. Km determinations were carried out for both PON1192 alloforms (Figure 3). This allows for the calculation of OP hydrolytic rates at any in vivo substrate concentration from rates measured in vitro at saturating non-OP substrate concentration. Table I shows the comparison of catalytic efficiency of hydrolysis of different OP compounds by each of the PON192 alloforms and the relationship between catalytic efficiency and resistance to OP compounds (34). Further details of the injection experiments and determination of the time course of plasma activity following PON1 injection into PON1-/- mice are found in Stevens et al. (27) and Li et al. (28). Figure 4 shows examples of the plots that were used to generate the conversion factors shown in Table II that allow rates of hydrolysis of non-OP substrates to be converted to rates of in vivo OP hydrolysis at a given substrate concentration when used with the Km values for specific OP hydrolysis by each PON1192 alloform and the Michaelis Menten equation (32). 137 In Parameters for Pesticide QSAR and PBPK/PD Models for Human Risk Assessment; Knaak, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Figure 2. Comparison of the 2 protocols for determining PON1 status. A, Assays using the highly toxic OP substrates DZO and PO. B, Assays using the non-OP substrates PA and CMPA. (○) indicates PON1Q/Q192; (■), PON1Q/R192; (Δ), PON1R/R192. Reproduced with permission from reference (31). Copyright 2008 Elsevier.

138 In Parameters for Pesticide QSAR and PBPK/PD Models for Human Risk Assessment; Knaak, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Figure 3. Substrate dependence of DZO hydrolysis by A, a PON1Q192 plasma sample (Km=0.52 mM); B, a PON1R192 plasma sample (Km=0.27 mM) and for CPO hydrolysis by C, a PON1Q192 plasma sample (Km=168 µM) and D, a PON1R192 plasma sample (Km=109 µM). The plasma samples were matched for rates of AREase activity. The substrate concentrations are indicated in the graphs and only the initial linear rates of hydrolysis were used for kinetic analyses. The closed symbols indicate rates of hydrolysis (υ) at the indicated substrate concentration and the open symbols are the [S] /υ reciprocal values for each of the rate data points (υ). Km values were determined from the x-axis intercepts of the [S] /υ vs. [S] plots (33). Reproduced with permission from reference (32). Copyright 2009 Elsevier.


Table I. atalytic efficiency determines the in vivo efficacy of PON1 for detoxifying OP compounds

140


Paraoxon PON1+/+

PON1-/-

Injected PON1192

Diazoxon PON1-/-

+192Q

+192R

PON1+/+

PON1-/-

Chlorpyrifos-oxon PON1-/-

PON1+/+

+192Q

+192R

aBrain

PON1-/-

PON1-/+192Q

+192R

ChE activity (% of control)

77 ± 15

53 ± 13

41 ± 9

34 ± 11

102 ± 5

20 ± 7

68 ± 22

81 ± 17

n.d. at 2 mg/kg?

14 ± 1

28 ± 11

87 ± 13

aDiaphragm ChE activity (% of control)

75 ± 18

57 ± 7

54 ± 8

57 ± 12

55 ± 4

22 ± 7

47 ± 13

56 ± 13

n.d. at 2 mg/kg?

19 ± 3

47 ± 5

77 ± 15

-

-

0.81

0.52

-

-

2.98

1.02

-

-

0.54

0.25

-

-

0.57

3.26

-

-

222

79

-

-

82

64

-

-

0.71

6.27

-

-

75

77

-

-

152

256

bKm

(mM)

bVmax

(units/mg)

bCatalytic

efficiency (Vmax/Km)

a Toxicity (ChE inhibition) associated with dermal exposure to OP compounds (0.3 mg/kg, paraoxon; 1 mg/kg, diazoxon; 2 mg/kg, chlorpyrifos-oxon) of wild-type (PON1+/+) and PON1 knockout (PON1-/-) mice, and of PON1-/- mice injected with either purified human PON1192Q (192Q) or PON1192R (192R) 4 hr prior to exposure. Data are expressed as percent ± SEM of ChE values for control mice receiving acetone alone. Note that only the columns of 192Q and 192R denote animals injected with each purified human PON1192 alloform. The columns labeled PON1+/+ and PON1-/- show the inhibition of brain and diaphragm ChE activity following exposures. Rows labeled b, list the kinetic parameters for hydrolysis of each OP by each PON1192 alloform (Q or R). b Paraoxonase, diazoxonase and chlorpyrifos-oxonase activities were determined in vitro (in 0.15 M NaCl), using purified human plasma PON1192Q or PON1192R isoforms (28). Units = µmol hydrolyzed/min. Adapted with permission from reference (34). Copyright 2003 Marcel Dekker, Inc.

In Parameters for Pesticide QSAR and PBPK/PD Models for Human Risk Assessment; Knaak, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Figure 4. Comparison of the rates of AREase hydrolysis measured at conditions of low salt (20 mM Tris-HCl, pH 8.0, 1 m M CaCl2) vs. CPOase, at physiological conditions (20 mM Tris-HCl, pH 7.4, 150 mM NaCl, 37°C) for samples of each PON1192 phenotype (A–C), and AREase hydrolysis measured at conditions of high salt (2 M NaCl, pH 8.0, 1 mM CaCl2, 23 °C) vs. CPOase, at physiological conditions (pH 7.4, 150 mM NaCl, 37 °C) for samples of each PON1192 phenotype (E–G). (○–○)=PON1Q/Q192 plasma samples, n=61; (■–■)=PON1Q/R192 plasma samples, n=49; (▵–▵)=PON1R/R192. plasma samples, n=18. Panel D=combined data from A–C; Panel H=Combined data from panels E–G. Reproduced with permission from reference (32). Copyright 2009 Elsevier.

Table II shows conversion factors that allow the interconversion of rates of hydrolysis of different substrates. (31, 32).


Table II. Conversion factors for rates of substrate hydrolysis*


Phenotype

Conversion Factors (U/ml) x 172 = DZOasephysc(U/L)

ar2

QQ

bAREaseHS

QR

AREaseHS (U/ml) x 204 = DZOasephys (U/L)

0.82

RR

AREaseHS (U/ml) x 286 = DZOasephys (U/L)

0.87

QQ

AREaseHS (U/ml) x 69 = CPOasephysd(U/L)

0.87

QR

AREaseHS (U/ml) x 103 = CPOasephys (U/L)

0.88

RR

AREaseHS (U/ml) x 189 = CPOasephys (U/L)

0.89

QQ

eAREaseLS

(U/ml) x 110 = DZOasephys (U/L)

0.84

QR

AREaseLS (U/ml) x 100 = DZOasephys (U/L)

0.72

RR

AREaseLS (U/ml) x 83 = DZOasephys (U/L)

0.93

QQ

AREaseLS (U/ml) x 45 = CPOasephys (U/L)

0.73

QR


0.84

RR


0.92

QQ

AREaseHS (U/ml) x 3.8 = POase (U/L)

0.75

QR


0.50

RR


0.90

QQ

fAREaseHS

(U/ml) x 1.6 = AREaseLS (U/ml)

0.85

QR

fAREaseHS


0.66

RR

fAREaseHS


0.83

QQ

DZOasephys (U/L) x 1.08 = DZOaseHSg (U/L)

0.90

QR

DZOasephys (U/L) x 1.01 = DZOaseHS (U/L)

0.91

RR

DZOasephys (U/L) x 0.84 = DZOaseHS (U/L)

0.87

0.93

a

Correlation coefficient squared. b AREaseHS = arylesterase activity measured in buffer and 2M NaCl. c DZOasephys = Diazoxonase activity measured under physiological conditions. d CPOasephys = Chlorpyrifos oxonase activity measured under physiological conditions. e AREaseLS = arylesterase activity measured in buffer. f From reference (31). g DZOaseHS = Diazoxonase activity measured at 2M NaCl, pH 8.5. * Reproduced with permission from reference (32). Copyright 2009 Elsevier.



In the case where bioactivation or bioinactivation of a specific drug by PON1 is of interest and where the assay is not amenable to a simple specrophotometric analysis, it will be useful to generate correlation plots for the three PON1192 phenotypes by comparing the rates of metabolism of the drug with rates of hydrolysis of a convenient PON1 substrate such as phenyl acetate. Then, for estimating the rate of PON1 catalysis of the given drug, measurement of phenyl acetate hydrolysis and determination of PON1 functional genotype or PON1 status and reference to a generated table should provide information useful for estimating an individualized drug dose based on the individual’s PON1 rate of inactivation or activation of the specific drug, provided that plasma PON1 is the major catalytic contributor to the metabolism of the drug in question. It should also be mentioned that “PON1 humanized mice” have also been generated with each of the PON1192 alloforms expressed in a PON1-/- strain, allowing for the characterization of human PON1192 alloforms under physiological conditions (29).

Summary Plasma PON1 provides an excellent example of developing approaches for estimating rates of in vivo substrate hydrolysis by serum enzymes using correlation factors established by kinetic characterization of the enzyme(s) carrying out the catalytic function. Often, assays of drug metabolism involve low throughput assays such as HPLC or LC/MS. By establishing factors (including Km values) that allow accurate conversion of convenient high throughput assay measures of hydrolysis of a different substrate to rates of difficult to measure drug bioactivation or inactivation, the low throughput assays should be replaceable by convenient high throughput assays. These analyses facilitate not only PBPK/PD studies, but are also useful in establishing risk of exposure (28) or disease (11, 12). The relationship between PON1 status and risk of disease is more complicated. PON1 and the two paralogs, PON2 and PON3 are encoded by tandem genes on the long arm of human chrosome 7 (35). All three of these related proteins are involved in modulating oxidative stress [reviewed in (36)] while only PON1 modulates exposure to some OP insecticides (9, 28). The protective mechanism of PON1 appears to be through both its ability to metabolize oxidized lipids as well as its peroxidase activity (37). While the rate constants presented here for PON1 are not yet applicable to accurately determining rates of metabolism of oxidized lipids or hydrogen peroxide in vivo, the activity of PON1 is clearly important in determining risk of vascular disease (e.g., (38–40)) and most likely other diseases where defects in the modulation of oxidative stress may increase the risk of disease. Recent studies reported by Besler et al. (39) demonstrated that healthy individuals had high levels of both plasma paraoxonase and arylesterase activities, whereas individuals with vascular disease had lower PON1 activity levels, but higher protein levels, suggesting that something is inactivating PON1 in individuals with vascular disease. The data also suggest that there is likely a feedback mechanism where the system is producing more PON1 protein to compensate for the lower activity. 143 In Parameters for Pesticide QSAR and PBPK/PD Models for Human Risk Assessment; Knaak, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


The possible relationship between the PON family of genes and neurological diseases is slowly coming into focus. Landers and colleagues reported that mutations in all three members of the PON family of genes appear to be risk factors for ALS (41). The relationship between PON1 status and risk of Parkinsons disease is quite complex in part due to exposures of mixtures of insecticides. For example, low PON1 status can result in the inhibition of carboxylesterase by an exposure to chlorpyrifos or diazoxon thus potentiating an exposure to malathion that is detoxified by carboxylesterases (42). One study sheds light on the interplay of PON1 status, brain cholinesterase activity and gene/protein expression. Cole et al. examined the consequence of genetic variability in PON1 status to chlorpyrifos oxon exposures during early development in the PON1 mouse model (43). The study revealed that low PON1 status for metabolism of chlorpyrifos oxon resulted in the disruption of multiple pathways and gene sets involved in mitochondrial dysfunction, oxidative stress, neurotransmission and nervous system development, explaining in part the oxidative stress component of OP exposure. A role of PON2 in modulating oxidative stress in brain was reported by Giordano et al. using a PON2 knockout (PON2-/-) mouse model to examine gene expression and PON2 activity in the brain (44). The highest levels of expression and activity were found in the substantia nigra, the nucleus accumbuns and the striatum with lower levels in the cerebral cortex, hippocampus, cerebellum and brainstem. PON2 was expressed primarily in microsomes and mitochondria. Toxicity of agents causing oxidative stress was higher in cells from the PON2-/mice. PON3 expression was not observed in brain and only low levels of PON1 were observed. Their results suggest a role of PON2 in protecting against oxidative stress in the brain. Two papers by Horke and colleagues provide additional insights into the role of PON2 in modulating oxidative stress. They observed that vascular PON2 reduced oxidative stress in vascular cells and decreased endoplasmic reticulum stress-induced caspase activation ((45), see also references cited therein). They also reported that PON2 is down regulated by a Pseudomonas aeuroginosa quorum-sensing factor (46). The later observation is quite interesting in contemplating the effect of a microbial infection inhibiting the modulation of oxidative stress in mitochondria. There are still important research needs regarding the function of the PON family of enzymes. PON1 status can be determined with the high throughput assays described here, however, it is not yet possible to do the same for PONs 2 and 3. Non-the-less, PON1 status analysis (activity and functional PON192 genotype) is much more informative than genotyping alone for determining the relationship between PON1 genetic variability and disease. One could genotype all ≈200 PON1 polymorphisms and not be able to predict PON1 activity levels (9). The important observation by Bessler et al. of high PON1 activity and low PON1 protein concentration in healthy patients; with low PON1 activity and high PON1 protein levels in individuals with vascular disease (39) points out the need to learn more about factors that may inactivate PON1. To date, there are no data on the relationship between an individual’s plasma PON1 activity level and liver PON1 activity. We do know, however, that the PON1-/- mice lack both plasma and liver PON1 activities (47). 144 In Parameters for Pesticide QSAR and PBPK/PD Models for Human Risk Assessment; Knaak, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

Sources of Funding This work was supported by National Institutes of Environmental Health Sciences (ES09883) (C Furlong), (ES04696) (H Checkoway), (ES07033) (D Eaton), and the National Heart, Lung, and Blood Institute (RO1 HL67406 and HL074366) (G Jarvik).

Conflicts of Interest The authors state no conflicts of interest.


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