國家衛生研究院 NHRI:Item 3990099045/4315
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    題名: The toxicity of mixtures of specific organophosphate compounds is modulated by paraoxonase 1 status
    其他題名: Advances in Experimental Medicine and Biology
    作者: Cole, TB;Jansen, K;Park, S;Li, WF;Furlong, CE;Costa, LG
    貢獻者: Division of Environmental Health and Occupational Medicine
    摘要: 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.
    日期: 2010-03-11
    關聯: Paraoxonases in Inflammation, Infection, and Toxicology. 2010 Mar 11;660:47-60.
    Link to: http://dx.doi.org/10.1007/978-1-60761-350-3_6
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000276140000006
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=77956550126
    顯示於類別:[李婉芬(2001-2009)] 期刊論文

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