Catalytic efficiency determines the in-vivo efficacy of PON1 for detoxifying organophosphorus compounds

Citation
Wf. Li et al., Catalytic efficiency determines the in-vivo efficacy of PON1 for detoxifying organophosphorus compounds, PHARMACOGEN, 10(9), 2000, pp. 767-779
Citations number
37
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
PHARMACOGENETICS
ISSN journal
0960-314X → ACNP
Volume
10
Issue
9
Year of publication
2000
Pages
767 - 779
Database
ISI
SICI code
0960-314X(200012)10:9<767:CEDTIE>2.0.ZU;2-6
Abstract
Human paraoxonase (PON1) is a polymorphic, high-density lipoprotein (HDL)-a ssociated esterase that hydrolyzes the toxic metabolites of several organop hosphorus (OP) insecticides and nerve agents. The activity polymorphism is determined by a Gln/Arg (Q/R) substitution at position 192, Injection of pu rified PON1 protects animals from OP poisoning. In the present study, we in vestigated the in-vivo function of PON1 for detoxifying organophosphorus in secticides in PON1-knockout mice that were challenged via dermal exposure w ith diazoxon, diazinon and paraoxon, PON1-knockout mice were extremely sens itive 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, Sur prisingly, these knockout mice did not show increased sensitivity to paraox on, bz-vitro assays indicated that the PON1(R192) isoform hydrolyzed diazox on less rapidly than did the PON1(Q192) isoform. In-vivo analysis, where PO N1-knockout mice received the same amount of either PON1(192) isoform via i ntraperitoneal (i.p.) injection 4 h prior to exposure, showed that both iso forms 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 n ot protect PON1-knockout mice from paraoxon toxicity, nor did over-expressi on 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 deto xication. The results indicate that PON1 plays a major role in the detoxica tion of diazoxon and chlorpyrifos oxon but not paraoxon. Pharmacogenetics 1 0:767-779 (C) 2000 Lippincott Williams & Wilkins.