The Toxicity of Mixtures of Specific Organophosphate Compounds is Modulated by Paraoxonase 1 Status

Abstract

Most chemical exposures involve complex mixtures. The role of paraoxonase 1 (PON1) and the Q192R polymorphism in the detoxication of individual organophosphorous (OP) compounds has been well-established. The extent to which PON1 protects against a given OP is determined by its catalytic efficiency. We used a humanized transgenic mouse model of the Q192R polymorphism to demonstrate that PON1 modulates the toxicity of OP mixtures by altering the activity of another detoxication enzyme, carboxylesterase (CaE). Chlorpyrifos oxon (CPO), diazoxon (DZO), and paraoxon (PO) are potent inhibitors of CaE, both in vitro and in vivo. We hypothesized that exposure of mice to these OPs would increase their sensitivity to the CaE substrate, malaoxon (MO), and that the degree of effect would vary among PON1 genotypes if the OP was a physiologically relevant PON1 substrate. When wild-type mice were exposed dermally to CPO, DZO, or PO and then, after 4 h, to different doses of MO, the toxicity of MO was increased compared to mice that received MO alone. The potentiation of MO toxicity by CPO and DZO was higher in PON1 knockout mice, which are less able to detoxify CPO or DZO. Potentiation by CPO was higher in Q192 mice than in R192 mice due to the decreased ability of PON1 Q192 to detoxify CPO. Potentiation by DZO was similar in the Q192 and R192 mice, due to their equivalent effectiveness at detoxifying DZO. PO exposure resulted in equivalent potentiation of MO toxicity among all four genotypes. These results indicate that PON1 status modulates the ability of CaE to detoxicate OP compounds from specific mixed insecticide exposures. PON1 status can also impact the capacity to metabolize drugs or other CaE substrates following insecticide exposure. KeywordsMixed exposures; Chlorpyrifos oxon; Chlorpyrifos oxon; Diazinon; Diazoxon; Malathion; Malaoxon; Parathion; Paraoxon; Pyrethroids; Tricresyl phosphate; Carboxylesterase; Paraoxonase 1 (PON1) PONand Detoxication of OP CompoundsThe involvement of paraoxonase 1 (PON1) in the detoxication of organophosphorus (OP) compounds has been well-documented (reviewed in Costa, 2006;. PON1 knockout (PON1 −/− ) mice are dramatically more sensitive than wild-type (PON1 +/+ ) mice to the toxicity of chlorpyrifos oxon (CPO) and diazoxon (DZO) and to a lesser extent the parent phosphorothioates, chlorpyrifos and diazinon (Shih et al. 1998;Li et al. 2000;Cole et al. 2005). Injection of purified plasma PON1 protein (Main, 1956;Costa et al. 1990;Li et al. 1995Li et al. , 2000 or, more recently, recombinant PON1 (Stevens et al. 2008), increased the resistance of rats and/or mice to OP toxicity. (Li et al. 2000). The Q192R amino acid polymorphism of PON1 (hPON1 Q192R ) affects the catalytic efficiency of hydrolysis for some substrates, but not others (Hassett et al. 1991;Adkins et al. 1993;Davies et al. 1996;Li et al. 2000). For diazoxon (DZO), the hPON1 Q192 and hPON1 R192 alloforms had equivalent catalytic efficiencies measured in vitro and injection of the hPON1 Q192 and hPON1 R192 alloforms p...

Neurobehavioral assessment of mice following repeated postnatal exposure to chlorpyrifos-oxon

“…These findings are consistent with our previous studies demonstrating that PON1 status plays a critical role in determining sensitivity to CPO and other OP insecticides (Cole et al, 2003, 2005, 2010; Jansen et al, 2009; Li et al, 2000). Remarkably, the neurobehavioral tests used in the current study did not show dramatic effects of repeated postnatal CPO exposure at the same dosages where effects were observed on cerebellar gene expression and AChE inhibition.…”

“…The common PON1 Q192R polymorphism affects the catalytic efficiency of hydrolysis of some substrates, including CPO, with PON1 R192 hydrolyzing CPO more efficiently than PON1 Q192 (Furlong, 2008; Li et al, 2000). Humanized transgenic mice expressing the PON1 Q192 alloform ( tgHuPON1 Q192 ) are more sensitive to CPF and CPO than mice expressing the human PON1 R192 alloform ( tgHuPON1 R192 ) (Cole et al, 2003, 2005), and are also more sensitive to the interactive toxicity of mixtures of OP compounds that include CPO (Cole et al, 2010; Jansen et al, 2009). PON1 knockout ( PON1 − / − ) mice are dramatically more sensitive than wild-type ( PON1 +/+ ) mice to the toxicity of CPO and diazoxon (DZO) (Furlong, 2008; Li et al, 2000; Shih et al, 1998), and thus represent a particularly sensitive model for assessing the toxicity of these compounds.…”

Kinetics and speciation of paraoxon hydrolysis by zinc(II)–azamacrocyclic catalysts

“…A more thorough analysis using Eqs. (2)(3)(4) reveals why values of s DEP diverge from s when considering the Zn 2+ -cyclam, Zn 2+ - [9]aneN 3 , and control samples: for less effective catalysts with smaller initial /, E4NPP formation becomes more important. However, the rate of formation of E4NPP is largely invariant among samples, having an average value of 0.596 ± 0.056 Â 10 À4 min À1 .…”

“…In spite of their usefulness as agricultural pest deterrents, organophosphorus (OP) pesticides are known to possess physical and chemical properties which cause detrimental environmental and physiological effects [1][2][3]. For example, many OPs have high boiling points and are relatively unreactive, making them potentially persistent environmental hazards [4,5].…”

Characterization of human paraoxonase 1 variants suggest that His residues at 115 and 134 positions are not always needed for the lactonase/arylesterase activities of the enzyme

“…Animals deficient in PON1 are more sensitive to OP‐poisoning and administration of purified exogenous PON1 have been shown to provide protection against OP‐poisoning . In humans the level and the activity of plasma PON1 have a major impact on the individual's susceptibility to OP‐poisoning . Thus, h‐PON1 is considered as a new generation antidote (catalytic bioscavenger candidate) for the pre‐treatment and therapy of OP pesticides and CWNA poisoning in humans …”