Quantitative Measurement of Inhibition of the Enzymatic Detoxification of Malathion by EPN (ethyl p-nitrophenyl thionobenzenephosphonate).

Murphy, Sheldon D.; DuBois, Kenneth P.

doi:10.3181/00379727-96-23617

Cited by 78 publications

(18 citation statements)

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“…Of particular relevance are early studies demonstrating that toxicity associated with exposure to malathion or its oxon metabolite, malaoxon (MO), was potentiated when the exposure occurred in combination with compounds that inhibit carboxylesterases (CaEs) (Aldridge, 1954; Cook et al 1957; Dubois, 1958; Murphy et al 1959; Seume and O’Brien, 1960; Casida et al 1961, 1963; Cohen and Murphy, 1971a;b; Verschoyle et al 1982). Malathion is converted in the liver to MO, which can be a potent inhibitor of AChE (DuBois et al 1953; March et al 1956; Murphy and DuBois, 1957; O’Brien, 1957), yet potentiation of malathion/MO toxicity was observed even at doses that would not normally inhibit acetylcholinesterase activity (Dubois, 1969; Su et al 1971). CaEs hydrolyze the carboxylic esters of malathion and MO (March et al 1956; O’Brien, 1957; Cook and Yip, 1958; Chen et al 1969).…”

Section: Toxicity Of Op Mixturesmentioning

confidence: 99%

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

Cole

Jansen

Park

et al. 2009

Advances in Experimental Medicine and Biology

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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...

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Section: Toxicity Of Op Mixturesmentioning

confidence: 99%

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

Cole

Jansen

Park

et al. 2009

Advances in Experimental Medicine and Biology

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“…CaEs can catalytically hydrolyze the carboxylic esters of malathion and MO (March et al, 1956; O’Brien, 1957; Cook and Yip, 1958; Chen et al, 1969). The bioactivation of malathion to its oxon analog forms a potent direct inhibitor of AChE (DuBois et al, 1953; March et al, 1956; Murphy and DuBois, 1957; O’Brien, 1957). When MO and CaE are combined in vitro , MO can act as both a substrate for hydrolysis and as an irreversible inhibitor of CaE and the rate of each reaction is affected by the other (Main and Dauterman, 1967).…”

Section: Introductionmentioning

confidence: 99%

Paraoxonase 1 (PON1) modulates the toxicity of mixed organophosphorus compounds

Jansen

Cole

Park

et al. 2009

Toxicology and Applied Pharmacology

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A transgenic mouse model of the human hPON1 Q192R polymorphism was used to address the role of paraoxonase (PON1) in modulating toxicity associated with exposure to mixtures of organophosphorus (OP) compounds. Chlorpyrifos oxon (CPO), diazoxon (DZO), and paraoxon (PO) are potent inhibitors of carboxylesterases (CaE). We hypothesized that a prior exposure to these OPs would increase sensitivity to malaoxon (MO), a CaE substrate, and the degree of the effect would vary among PON1 genotypes if the OP was a physiologically significant PON1 substrate in vivo. CPO and DZO are detoxified by PON1. For CPO hydrolysis, hPON1 R192 has a higher catalytic efficiency than hPON1 Q192 . For DZO hydrolysis, the two alloforms have nearly equal catalytic efficiencies. For PO hydrolysis, the catalytic efficiency of PON1 is too low to be physiologically relevant. When wild-type mice were exposed dermally to CPO, DZO, or PO followed 4-h later by increasing doses of MO, toxicity was increased compared to mice receiving MO alone, presumably due to CaE inhibition. Potentiation of MO toxicity by CPO and DZO was greater in PON1 −/− mice, which have greatly reduced capacity to detoxify CPO or DZO. Potentiation by CPO was more pronounced in hPON1 Q192 mice than in hPON1 R192 mice due to the decreased efficiency of hPON1 Q192 for detoxifying CPO. Potentiation by DZO was similar in hPON1 Q192 and hPON1 R192 mice, which are equally efficient at hydrolyzing DZO. Potentiation by PO was equivalent among all four genotypes. These results indicate that PON1 status can have a major influence on CaE-mediated detoxication of OP compounds.

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“…Potentiation of action between organophosphates is known since long ago (Frawley et a/. 1957;Murphy & Du Bois 1957;Cohen & Murphy 1970;Cook etal. 1958;Cohen & Murphy 1971).…”

Section: Discussionmentioning

confidence: 99%

Levels of Metrifonate and Dichlorvos in Plasma and Erythrocytes during Treatment of Schistosomiasis with Bilarcil®

Nordgren

Bengtsson

Holmstedt

et al. 1981

Acta Pharmacologica et Toxicologica

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A method for the simultaneous quantitation of metrifonate (0,0‐dimethyl‐(1‐hydroxy‐2,2,2‐trichloroethyl)‐phosphonate) and dichlorvos (2,2‐dichlorovinyl dimethyl phosphate, DDVP) in human blood has been worked out. It is based upon multiple labelling of the compounds with deuterium and gas phase analysis using the mass spectrometer as a selective detector. The amount of DDVP in plasma is about 1% of the amount of metrifonate. In erythrocytes the corresponding amount of DDVP is 0.5% or less of metrifonate. Both compounds reach peak levels in blood within two hours after oral dosing and are detectable for at least eight hours. Cholinesterase activity in plasma reaches zero levels within 15 min. and remains inhibited for more than eight hours. Red blood cell cholinesterase is inhibited only 60‐80%. According to kinetic calculations, clearance of metrifonate occurs primarily via dichlorvos. If dichlorvos is the only active component, which in all likelihood it is, it's slow release may be important in the schistosomicidal effect. Clinical data in seven metrifonate treated patients revealed that mild vertigo subsiding in a few hours was the most common side effect.

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Quantitative Measurement of Inhibition of the Enzymatic Detoxification of Malathion by EPN (ethyl p-nitrophenyl thionobenzenephosphonate).

Cited by 78 publications

References 0 publications

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

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

Paraoxonase 1 (PON1) modulates the toxicity of mixed organophosphorus compounds

Levels of Metrifonate and Dichlorvos in Plasma and Erythrocytes during Treatment of Schistosomiasis with Bilarcil®

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