Paraoxonase 1 (PON1) status and substrate hydrolysis

被引：95

作者：

Richter, Rebecca J.

Jarvik, Gail P.

Furlong, Clement E. ^{[1
]}

机构：

[1] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA

来源：

TOXICOLOGY AND APPLIED PHARMACOLOGY | 2009年 / 235卷 / 01期

关键词：

Paraoxonase; 1; PON1; polymorphism; Chlorpyrifos; Chlorpyrifos axon; Diazinon; Diazoxon; Pharmacogenetics; HUMAN-SERUM PARAOXONASE; CORONARY-HEART-DISEASE; Q192R POLYMORPHISM; CHLORPYRIFOS OXON; MOLECULAR-BASIS; ARYLESTERASE; EXPRESSION; GENE; TOXICITY; PROMOTER;

D O I：

10.1016/j.taap.2008.11.001

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Paraoxonase 1 (PON1) hydrolyzes a number of organophosphorus (OP) compounds including insecticides and nerve agents. The in vivo efficacy of PON1 to protect against a specific OP exposure depends on the catalytic efficiency of hydrolysis. The Q192R polymorphism affects the catalytic efficiency of hydrolysis of some substrates and not others. While PON1(R192) hydrolyzes paraoxon approximately 9-times as efficiently as PON1(Q192), the efficiency is insufficient to provide in vivo protection against paraoxon/parathion exposure. The two PON1(192) alloforms have nearly equivalent but higher catalytic efficiencies for hydrolyzing diazoxon (DZO) and provide equivalent in vivo protection against DZO exposures. On the other hand, PON1(R192) is significantly more efficient in hydrolyzing chlorpyrifos oxon (CPO) than PON1(Q192) and provides better protection against CPO exposure. Thus, for some exposures it is only the level of plasma PON1 that is important, whereas for others it is both plasma level and the PON1(192) alloform(s) present in plasma that are important. In no case is the plasma level of PON1 unimportant, provided that the catalytic efficiency is sufficient to protect against the exposure. Two-substrate enzyme assay/analysis protocols that reveal both PON1 plasma levels and PON1(192) phenotype (QQ; QR; RR) are designed to optimize the separation of PON1(192) phenotypes; however, they have not been optimized for evaluating in vivo rates of OP detoxication. This study describes the adaptation of a non-OP, two-substrate determination of PON1 status to the conversion of the PON1 status data to physiologically relevant rates of DZO and CPO detoxication. Conversion factors were generated for rates of hydrolysis of different substrates. (C) 2008 Elsevier Inc. All rights reserved.

引用

页码：1 / 9

页数：9

共 54 条

[11] Paraoxonase-1 promoter haplotypes and serum paraoxonase: a predominant role for polymorphic position-107, implicating the Sp1 transcription factor [J].

Deakin, S ;

Leviev, I ;

Brulhart-Meynet, MC ;

James, RW .

BIOCHEMICAL JOURNAL, 2003, 372 (372) :643-649

[12] Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1 [J].

Deakin, SP ;

James, RW .

CLINICAL SCIENCE, 2004, 107 (05) :435-447

[13]

DIEPGEN TL, 1986, ARCH TOXICOL, P154

[14]

DOWD JE, 1965, J BIOL CHEM, V240, P863

[15]

ECKERSON HW, 1983, AM J HUM GENET, V35, P1126

[16]

ECOBICHON DJ, 1973, CLIN PHARMACOL THER, V14, P41

[17] The functional consequences of polymorphisms in the human PON1 gene [J].

Furlong, C. E. ;

Richter, R. J. ;

Li, W. -F. ;

Brophy, V. H. ;

Carlson, C. ;

Rieder, M. ;

Nickerson, D. ;

Costa, L. G. ;

Ranchalis, J. ;

Lusis, A. J. ;

Shih, D. M. ;

Tward, A. ;

Jarvik, G. P. .

PARAOXNASES: THEIR ROLE IN DISEASE DEVELOPMENT AND XENOBIOTIC METABOLISM, 2008, 6 :267-+

[18] PURIFICATION OF RABBIT AND HUMAN SERUM PARAOXONASE [J].

FURLONG, CE ;

RICHTER, RJ ;

CHAPLINE, C ;

CRABB, JW .

BIOCHEMISTRY, 1991, 30 (42) :10133-10140

[19]

Furlong CE, 2006, PHARMACOGENET GENOM, V16, P183

[20]

GAN KN, 1991, DRUG METAB DISPOS, V19, P100

← 1 2 3 4 5 6 →