SERUM PARAOXONASE STATUS - A MAJOR FACTOR IN DETERMINING RESISTANCE TO ORGANOPHOSPHATES
SERUM PARAOXONASE STATUS - A MAJOR FACTOR IN DETERMINING RESISTANCE TO ORGANOPHOSPHATES
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DOI：
10.1080/15287399309531798
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发表时间：
1993-10-01
期刊：
影响因子：
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通讯作者：
FURLONG, CE
中科院分区：
文献类型：
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作者：
LI, WF;COSTA, LG;FURLONG, CE
许多证据表明，血清对氧磷酶对这种酶的有机磷底物中毒具有保护作用。血清中对氧磷水解活性水平极低的鸟类对氯磷中毒非常敏感。兔子的酶水平比老鼠高7倍，对对氧磷中毒的抵抗力比老鼠高4倍。兔对氧磷酶水解毒死蜱-氧磷的周转数比大鼠对氧磷酶高得多，导致兔对毒死蜱毒性具有非常高的抗性。对氧磷酶保护作用的直接试验是通过将纯化的兔酶注射到大鼠体内进行的。达到的保护是较高的毒死蜱，氧磷比对氧磷，可能是由于高水解活性的毒死蜱，氧磷的兔酶。在人类中，观察到血清对氧磷酶的底物依赖性多态性，其中对氧磷酶的一种亚型对氧磷具有高转换数，而另一种亚型对氧磷具有低转换数。这两种异构体似乎以相同的速率水解毒死蜱-氧磷和苯乙酸盐。对氧磷酶cDNA的克隆和序列分析阐明了多态性的分子基础。192位的精氨酸决定高对氧磷酶活性，而该位置的谷氨酰胺决定低对氧磷酶活性。除了多态性外，在给定的遗传类别内，还可以看到血清酶水平的13倍变化。本文报道的实验表明，注射到小鼠体内的兔对氧磷酶可保护小鼠免受母体杀虫剂毒死蜱和有毒氧磷的侵害。这些结果表明，血清对氧磷酶状态可能作为一个生物标志物的杀虫剂在人类的敏感性。
A number of lines of evidence suggest that serum paraoxonase is protective against poisoning by organophosphorus substrates of this enzyme. Birds that have very low levels of paraoxon hydrolyzing activity in their sera are very susceptible to parathion poisoning. Rabbits, which have a sevenfold higher enzyme level compared with rats, have a fourfold higher resistance to paraoxon poisoning than rats. Rabbit paraoxonase hydrolyzes chlorpyrifos-oxon with a much higher turnover number than does rat paraoxonase, resulting in a very high resistance of rabbits to chlorpyrifos toxicity. Direct tests of paraoxonase protection have been carried out by injecting purified rabbit enzyme into rats. The protection achieved was higher for chlorpyrifos-oxon than for paraoxon, probably due to the high hydrolytic activity of the rabbit enzyme for chlorpyrifos-oxon. In humans, a substrate-dependent polymorphism of serum paraoxonase is observed, where one isoform of paraoxonase has a high turnover number for paraoxon and the other a low turnover number. Both isoforms appear to hydrolyze chlorpyrifos-oxon and phenylacetate at the same rate. Cloning and sequencing of the human paraoxonase cDNAs has elucidated the molecular basis of the polymorphism. Arginine at position 192 determines high paraoxonase activity, and glutamine at this position, low paraoxonase activity. In addition to the polymorphism, a 13-fold variation in serum enzyme levels within a given genetic class is seen. The experiments reported here demonstrate that rabbit paraoxonase injected into mice provides protection against the parent insecticide chlorpyrifos as well as the toxic oxon. These results suggest that serum paraoxonase status may serve as a biomarker for insecticide susceptibility in humans.