期刊
PHARMACOGENETICS
卷 10, 期 9, 页码 767-779出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/00008571-200012000-00002
关键词
PON1; diazinon; diazoxon; paraoxon; chlorpyrifos
资金
- NIEHS NIH HHS [P30 ES07033, ES09883, 1 PO1 ES09601-01] Funding Source: Medline
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 the in-vivo function of PON1 for detoxifying organophosphorus insecticides in PON1-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, bz-vitro assays indicated that the PON1(R192) isoform hydrolyzed diazoxon less rapidly than did the PON1(Q192) isoform. In-vivo analysis, where PON1-knockout mice received the same amount of either PON1(192) isoform via intraperitoneal (i.p.) injection 4 h prior to exposure, showed that both isoforms provided a similar degree of protection against diazoxon, while PON1(R192) conferred better protection against chlorpyrifos-oxon than PON1(Q192). Injection of purified rabbit PON1 or either human PON1(192) isoform did not protect PON1-knockout mice from paraoxon toxicity, nor did over-expression of the human PON1(R192) transgene in wild-type mice. Kinetic analysis of the two human PON1(192) isoforms revealed that the catalytic efficiency (V-max/K-m) determines the in-vivo efficacy 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. Pharmacogenetics 10:767-779 (C) 2000 Lippincott Williams & Wilkins.
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