Paraoxonase (PON1), a HDL-associated enzyme, protects against toxicity from specific organophosphorus compounds and oxidized lipids. Common polymorphisms in the PON1 gene have been identified and characterized in the coding region, 5′ regulatory region and 3′ UTR. The Q192R coding region polymorphism determines substrate-dependent differences in catalytic efficiency of hydrolysis. The −108CT polymorphism in the 5′ regulatory region has a significant effect on PON1 expression, with the −108C allele expressing on average twice the level of plasma PON1 as the −108T allele. In addition to the effects of regulatory and coding region polymorphisms on PON1 levels and activity, plasma PON1 levels are also developmentally regulated. Since PON1 levels are important in determining resistance to specific organophosphorus compounds, the time course of appearance of PON1 in newborns is of great interest.
We report here that PON1 levels plateau between 6 to 15 months of age, and that variability in the age at which PON1 levels plateau is quite variable among individuals. In mice and rats, plasma PON1 activity reaches a plateau at 3 weeks of age. In mice that lack endogenous PON1, human transgenes encoding either PON1 Q192 or PON1 R192 under the control of the human PON1 regulatory sequences exhibited a similar time course of expression as that seen in wild-type mice, indicating conservation of the developmental regulatory elements between mouse and human PON1.
Departments of aEnvironmental Health, bMedicine, Division of Medical Genetics, cGenome Sciences, University of Washington, Seattle, WA, USA, dDepartment of Microbiology and Molecular Genetics, and Division of Cardiology, Department of Medicine, UCLA School of Medicine, Los Angeles, CA, USA and eChildren's Hospital and Regional Medical Center, Seattle, WA, USA.
Corresponding author: C.E. Furlong, University of Washington, Division of Medical Genetics, Box 357720, Seattle, WA 98195-7720. Fax: +1 206 543 3050; e-mail: email@example.com
Received 24 January 2003 Accepted 29 March 2003
*Current address: UCSF Hooper Foundation, San Francisco, CA 94143-0552. Sources of support: ES09883, ES07033, ES-09601/EPA-R826886, ES04696, T32-AG00057, HL30568.