Furlong C E, Li W F, Brophy V H, Jarvik G P, Richter R J, Shih D M, Lusis A J, Costa L G
Department of Genetics, University of Washington, Seattle, USA.
Neurotoxicology. 2000 Aug;21(4):581-7.
It has been assumed since its discovery that serum paraoxonase (PON1) plays a major role in the detoxication of specific organophosphorus compounds. It was also assumed that individuals with low PON1 activity would be more susceptible to paraoxon/parathion poisoning than individuals with higher PON1 activity. Evidence supporting this hypothesis was provided by injection of rabbit PON1 into rodents. Injected PON1 protected against paraoxon toxicity in rats and chlorpyrifos oxon toxicity in mice. The recent availability of PON1 knockout mice has provided an in vivo system with which one can more closely examine the role of PON1 in detoxication. PON1 knockout mice demonstrated dramatically increased sensitivity to chlorpyrifos oxon and diazoxon and moderately increased sensitivity to the respective parent compounds. The PON1 knockout mutation also resulted in the elimination of liver PON1 activity, accounting for the dramatic increase in sensitivity to chlorpyrifos oxon and diazoxon. Totally unexpected was our finding that the PON1 knockout mice were not more sensitive to paraoxon. This was particularly surprising in light of the earlier enzyme injection experiments. Differences in the relative catalytic efficiencies of rabbit vs. mouse PON1 for the specific oxon forms explain these observations. Mouse PON1 has good catalytic efficiency for the hydrolysis of diazoxon and chlorpyrifos oxon, but a poor efficiency for paraoxon hydrolysis relative to rabbit PON1. The human PON1Q192 isoform has a catalytic efficiency similar to that of mice, whereas the human PON1R192 isoform has a much better catalytic efficiency, predicting that individuals expressing high levels of the PONIR192 isoform may have increased resistance to paraoxon toxicity.
自发现以来，人们一直认为血清对氧磷酶（PON1）在特定有机磷化合物的解毒过程中起主要作用。人们还认为，与PON1活性较高的个体相比，PON1活性较低的个体更容易受到对氧磷/对硫磷中毒的影响。将兔PON1注射到啮齿动物体内为这一假设提供了证据。注射的PON1可保护大鼠免受对氧磷毒性的影响，并保护小鼠免受毒死蜱氧磷毒性的影响。最近获得的PON1基因敲除小鼠提供了一个体内系统，通过该系统可以更密切地研究PON1在解毒中的作用。PON1基因敲除小鼠对毒死蜱氧磷和二嗪磷的敏感性显著增加，对各自的母体化合物的敏感性适度增加。PON1基因敲除突变还导致肝脏PON1活性的消除，这解释了对毒死蜱氧磷和二嗪磷敏感性的显著增加。我们发现PON1基因敲除小鼠对对氧磷并不更敏感，这完全出乎意料。鉴于早期的酶注射实验，这尤其令人惊讶。兔PON1与小鼠PON1对特定氧磷形式的相对催化效率的差异解释了这些观察结果。小鼠PON1对二嗪磷和毒死蜱氧磷的水解具有良好的催化效率，但相对于兔PON1，对对氧磷水解的效率较差。人PON1Q192同工型的催化效率与小鼠相似，而人PON1R192同工型的催化效率要好得多，这预测表达高水平PON1R192同工型的个体可能对对氧磷毒性具有更高的抗性。
