Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis

• Published in: Nature (London) 1998-07, Vol.394 (6690), p.284-287
• Main Authors: Lusis, Aldons J, Shih, Diana M, Gu, Lingjie, Xia, Yu-Rong, Navab, Mohamad, Li, Wan-Fen, Hama, Susan, Castellani, Lawrence W, Furlong, Clement E, Costa, Lucio G, Fogelman, Alan M
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Aorta - pathology; Arteriosclerosis - etiology; Arteriosclerosis - pathology; Aryldialkylphosphatase; Biological and medical sciences; Cells, Cultured; Chlorpyrifos - analogs & derivatives; Chlorpyrifos - toxicity; Cholinesterase Inhibitors - toxicity; Coculture Techniques; Diet, Atherogenic; Enzymes and enzyme inhibitors; Esterases - blood; Esterases - deficiency; Esterases - genetics; Esterases - physiology; Female; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; Humans; Hydrolases; Inactivation, Metabolic; Insecticides - toxicity; letter; Lipid Peroxides - blood; Lipid Peroxides - metabolism; Lipoproteins, HDL - blood; Lipoproteins, HDL - metabolism; Lipoproteins, LDL - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Oxidation-Reduction; Restriction Mapping; Risk Factors; Science; Science (multidisciplinary)
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/28406

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 chlorpyrifos. PON1 may also confer protection against coronary artery disease by destroying pro-inflammatory oxidized lipids present in oxidized low-density lipoproteins (LDLs). 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.