Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis.
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.
Shih
D M
DM
Division of Cardiology, Department of Medicine, UCLA School of Medicine, Los Angeles, California 90095, USA.
Gu
L
L
Xia
Y R
YR
Navab
M
M
Li
W F
WF
Hama
S
S
Castellani
L W
LW
Furlong
C E
CE
Costa
L G
LG
Fogelman
A M
AM
Lusis
A J
AJ
D000818:Animals; D001011:Aorta / Q000473:pathology; D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology; D043303:Aryldialkylphosphatase; D002478:Cells, Cultured; D004390:Chlorpyrifos / Q000031:analogs & derivatives / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D018920:Coculture Techniques; D004036:Diet, Atherogenic; D004950:Esterases / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D007306:Insecticides / Q000633:toxicity*; D008054:Lipid Peroxides / Q000097:blood / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D015183:Restriction Mapping; D012307:Risk Factors
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D008054:Lipid Peroxides; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; C009618:O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; D004950:Esterases; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D004390:Chlorpyrifos