Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis

Diana M. Shih, Lingjie Gu, Yu-Rong Xia, Mohamad Navab, Wan-Fen Li, Susan Hama, Lawrence W. Castellani, Clement E. Furlong, Lucio G. Costa, Alan M. Fogelman and Aldons J. Lusis ()
Additional contact information
Diana M. Shih: 47-123 CHS, UCLA School of Medicine
Lingjie Gu: 47-123 CHS, UCLA School of Medicine
Yu-Rong Xia: 47-123 CHS, UCLA School of Medicine
Mohamad Navab: 47-123 CHS, UCLA School of Medicine
Wan-Fen Li: University of Washington
Susan Hama: 47-123 CHS, UCLA School of Medicine
Lawrence W. Castellani: 47-123 CHS, UCLA School of Medicine
Clement E. Furlong: University of Washington
Lucio G. Costa: University of Washington
Alan M. Fogelman: 47-123 CHS, UCLA School of Medicine
Aldons J. Lusis: 47-123 CHS, UCLA School of Medicine

Nature, 1998, vol. 394, issue 6690, 284-287

Abstract: Abstract Serum paraoxonase (PON1) is an esterase that is associated with high-density lipoproteins (HDLs) in the plasma; it is involved in the detoxification of organophosphate insecticides such as parathion and chlorpyrifos1,2,3. PON1 may also confer protection against coronary artery disease by destroying pro-inflammatory oxidized lipids present in oxidized low-density lipoproteins (LDLs)4,5,6,7,8. To study the role of PON1 in vivo, we created PON1 -knockout mice by gene targeting. Compared with their wild-type littermates, PON1-deficient mice were extremely sensitive to the toxic effects of chlorpyrifos oxon, the activated form of chlorpyrifos, and were more sensitive to chlorpyrifos itself. HDLs isolated from PON1-deficient mice were unable to prevent LDL oxidation in a co-cultured cell model of the artery wall, and both HDLs and LDLs isolated from PON1 -knockout mice were more susceptible to oxidation by co-cultured cells than the lipoproteins from wild-type littermates. When fed on a high-fat, high-cholesterol diet, PON1 -null mice were more susceptible to atherosclerosis than their wild-type littermates.

Date: 1998
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DOI: 10.1038/28406

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