Catalytic efficiency determines thein-vivoefficacy of PON1 for detoxifying organophosphorus compounds
作者:
Wan-Fen Li,
Lucio Costa,
Rebecca Richter,
Tamara Hagen,
Diana Shih,
Aaron Tward,
Aldon Lusis,
Clement Furlong,
期刊:
Pharmacogenetics
(OVID Available online 2000)
卷期:
Volume 10,
issue 9
页码: 767-779
ISSN:0960-314X
年代: 2000
出版商: OVID
关键词: PON1;diazinon;diazoxon;paraoxon;chlorpyrifos
数据来源: OVID
摘要:
Human paraoxonase (PON1) is a polymorphic, high-density lipoprotein (HDL)-associated esterase that hydrolyzes the toxic metabolites of several organophosphorus (OP) insecticides and nerve agents. The activity polymorphism is determined by a Gln/Arg (Q/R) substitution at position 192. Injection of purified PON1 protects animals from OP poisoning. In the present study, we investigated thein-vivofunction of PON1 for detoxifying organophosphorus insecticides inPON1-knockout mice that were challenged via dermal exposure with diazoxon, diazinon and paraoxon.PON1-knockout mice were extremely sensitive to diazoxon. Doses (2 and 4 mg/kg) that caused no cholinesterase (ChE) inhibition in wild-type mice were lethal to the knockout mice, which also showed slightly increased sensitivity to the parent compound diazinon. Surprisingly, these knockout mice did not show increased sensitivity to paraoxon.In-vitroassays indicated that the PON1R192isoform hydrolyzed diazoxon less rapidly than did the PON1Q192isoform.In-vivoanalysis, wherePON1-knockout mice received the same amount of either PON1192isoform via intraperitoneal (i.p.) injection 4 h prior to exposure, showed that both isoforms provided a similar degree of protection against diazoxon, while PON1R192conferred better protection against chlorpyrifos–oxon than PON1Q192. Injection of purified rabbit PON1 or either human PON1192isoform did not protectPON1-knockout mice from paraoxon toxicity, nor did over-expression of the humanPON1R192transgene in wild-type mice. Kinetic analysis of the two human PON1192isoforms revealed that the catalytic efficiency (Vmax/Km) determines thein-vivoefficacy of PON1 for organophosphorus detoxication. The results indicate that PON1 plays a major role in the detoxication of diazoxon and chlorpyrifos oxon but not paraoxon.
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