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Paraoxonase 1 (PON1) status affects the metabolism of drugs and insecticides.

Authors
Furlong-CE; Cole-TB; Pettan-Brewer-C; Shih-DM; Tward-A; Lusis-AJ; Timchalk-C; Richter-RJ; Costa-LG
Source
Drug Metab Rev 2005 Oct; 37(Suppl 2):21-22
NIOSHTIC No.
20033145
Abstract
The highly polymorphic human PON1 gene has approximately 200 polymorphisms identified to date. The C-108T polymorphism influences PON1 levels with the C-108 allele producing on average approximately 2 x more PON1 than T-108. The Q 192R coding region polymorphism affects the catalytic efficiency of hydrolysis of some but not all PON1 substrates. Individual plasma PON1 levels vary 13-fold in adults. Newborns have approximately 3-4-fold lower PON1 levels than adults. PON1-1- mice have approximately ", 10-fold greater sensitivity to diazoxon (DZO) and chorpyrifos oxon (CPO). Injecting purified human PON1-Q or RI92 restores resistance, with either alloform protecting equivalently against DZO exposure and PON1192 providing greater protection against CPO exposure. Toxicity studies in mice expressing human hPON1Q192 or hPON1R192 confirm the latter observation. This observation is of concern, since PON1Q192 homozygotes comprise up to 50% of most populations. PON1 status is determined with a 2-substrate assay/analysis where rates of DZO hydrolysis are plotted against rates, of paraoxon hydrolysis, clearly separating the three PON1192 functional phenotypes (QQ/QR/RR) and at the same lime providing measurement of plasma PON1 levels, both of which arc important in determining resistance to CPO exposures und required doses for drugs activated or inactivated by PON1.
Keywords
Metabolic-study; Metabolism; Pesticides; Pesticides-and-agricultural-chemicals; Insecticides; Enzymatic-effects; Enzyme-activity
CODEN
DMTRAR
Publication Date
20051001
Document Type
Abstract; Conference/Symposia Proceedings
Funding Amount
246279
Funding Type
Grant
Fiscal Year
2006
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-003629
ISSN
0360-2532
Priority Area
Research Tools and Approaches: Exposure Assessment Methods
Source Name
Drug Metabolism Reviews
State
WA
Performing Organization
Battelle Memorial Institute, Richland, Washington
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