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Review
. 2010:660:47-60.
doi: 10.1007/978-1-60761-350-3_6.

The toxicity of mixtures of specific organophosphate compounds is modulated by paraoxonase 1 status

Toby B Cole  1 , Karen Jansen, Sarah Park, Wan-Fen Li, Clement E Furlong, Lucio G Costa
Affiliations
Review

The toxicity of mixtures of specific organophosphate compounds is modulated by paraoxonase 1 status

Toby B Cole et al. Adv Exp Med Biol. 2010.

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.

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Figures

Fig. 1
Fig. 1
Time course of plasma CaE inhibition in vivo, following exposure to CPO, DZO, and PO. Time course of plasma carboxylesterase (CaE) inhibition in PON1+/+, PON1−/−, hPON1Q192,and hPON1R192 mice (genotypes as indicated) following dermal exposure to 0.75 mg/kg CPO (a), 0.5 mg/kg DZO (b), or 0.35 mg/kg PO (c). Maximal inhibition of CaE was at 4 hours. Results represent the mean ± SEM (n = 5–10). Reproduced from Jansen et al. (2009) with permission
Fig. 2
Fig. 2
Effect of CPO exposure (0.75 mg/kg) on subsequent toxicity of malaoxon (MO). Mice (genotypes as indicated) were exposed dermally to MO alone (a, b), or to CPO followed 4 hours later by MO exposure (c, d, e, f). AChE was measured in the brain (a, c, e) and diaphragm (b, d, f) 4 hours following the MO exposure. Results represent the mean ± SEM (n = 4). Reproduced from Jansen et al. (2009) with permission
Fig. 3
Fig. 3
Effect of DZO exposure (0.5 mg/kg) on subsequent toxicity of malaoxon (MO). Mice (genotypes as indicated) were exposed dermally to MO alone (a, b), or to DZO followed 4 hours later by MO exposure (c, d, e, f). AChE was measured in the brain (a, c, e) and diaphragm (b, d, f) 4 hours following the MO exposure. Results represent the mean ± SEM (n = 4). Reproduced from Jansen et al. (2009) with permission
Fig. 4
Fig. 4
Effect of PO exposure (0.35 mg/kg) on subsequent toxicity of malaoxon (MO). Mice (genotypes as indicated) were exposed dermally to MO alone (a, b), or to CPO followed 4 hours later by MO exposure (c, d, e, f). AChE was measured in the brain (a, c, e) and diaphragm (b, d, f) 4 hours following the MO exposure. Results represent the mean ± SEM (n = 4). Reproduced from Jansen et al. (2009) with permission
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References

    1. Abernathy CO, Casida JE. Pyrethroid insecticides: esterase cleavage in relation to selective toxicity. Science. 1973;179:1235–1236. - PubMed
    1. Adkins S, Gan KN, Mody M, La Du BN. Molecular basis for the polymorphic forms of human serum paraoxonase/arylesterase: glutamine or arginine at position 191, for the respective A or B allozymes. Am J Hum Genet. 1993;53:598–608. - PMC - PubMed
    1. Aldridge WN. Tricresyl phosphates and cholinesterase. Biochem J. 1954;56:185–189. - PMC - PubMed
    1. Buratti FM, Testai E. Malathion detoxication by human hepatic carboxylesterase and its inhibition by isomalathion and other pesticides. J Biochem Mol Toxicol. 2005;19:406–414. - PubMed
    1. Casida JE, Eto M, Baron RL. Biological activity of a tri-o-cresyl phosphate metabolite. Nature. 1961;191:1396–1397. - PubMed

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