Jansen Karen L, Cole Toby B, Park Sarah S, Furlong Clement E, Costa Lucio G
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
Toxicol Appl Pharmacol. 2009 Apr 15;236(2):142-53. doi: 10.1016/j.taap.2009.02.001. Epub 2009 Feb 9.
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.
人类对氧磷酶1（hPON1）（Q192R）多态性的转基因小鼠模型被用于研究对氧磷酶（PON1）在调节与接触有机磷（OP）化合物混合物相关的毒性中所起的作用。毒死蜱氧磷（CPO）、二嗪磷（DZO）和对氧磷（PO）是羧酸酯酶（CaE）的强效抑制剂。我们假设，预先接触这些有机磷化合物会增加对CaE底物马拉氧磷（MO）的敏感性，并且如果该有机磷化合物在体内是生理上重要的PON1底物，那么其影响程度在不同的PON1基因型之间会有所不同。CPO和DZO可被PON1解毒。对于CPO水解，hPON1（R192）的催化效率高于hPON1（Q192）。对于DZO水解，这两种同工型的催化效率几乎相等。对于PO水解，PON1的催化效率过低，不具有生理相关性。当野生型小鼠经皮肤接触CPO、DZO或PO，4小时后再给予递增剂量的MO时，与单独接受MO的小鼠相比，毒性增加，这可能是由于CaE受到抑制。在PON1基因敲除（-/-）小鼠中，CPO和DZO对MO毒性的增强作用更大，这些小鼠解毒CPO或DZO的能力大大降低。由于hPON1（Q192）解毒CPO的效率降低，CPO对hPON1（Q192）小鼠的增强作用比对hPON1（R192）小鼠更明显。DZO对hPON1（Q192）和hPON1（R192）小鼠的增强作用相似，这两种小鼠水解DZO的效率相同。PO对所有四种基因型的增强作用相当。这些结果表明，PON1状态可对有机磷化合物的CaE介导解毒产生重大影响。
