The paraoxonase gene family and coronary heart disease.
OBJECTIVE
The antioxidant activity of high-density lipoprotein is largely due to the paraoxonase 1 located on it. Experiments with transgenic paraoxonase 1 knock-out mice indicate the potential for this enzyme to protect against atherogenesis. This effect of high-density lipoprotein in decreasing low-density lipoprotein lipid peroxidation is maintained for longer than that of antioxidant vitamins and could thus be more protective. Several important advances in the field of paraoxonase research have occurred during this review period, not least the discovery that two other members of the paraoxonase gene family, PON2 and PON3, may also have important antioxidant properties. Significant advances have been made in understanding the basic biochemical function of paraoxonase 1 and the discovery of possible modulators of its activity.


RESULTS
Decreased coronary heart disease risk associated with polymorphisms of paraoxonase 1, which are most active in lipid peroxide hydrolysis, as revealed by meta-analysis is likely to be an underestimate of the true contribution of paraoxonase 1 to coronary heart disease because these polymorphisms explain only a small component of the variation in paraoxonase 1 activity. It is a very important observation, however, because genetic influences are not likely to be confounded by other factors linked with both coronary heart disease and diminished paraoxonase 1 activity.


CONCLUSIONS
Although advances have been made in research into the paraoxonase family and atherosclerosis, much more needs to be done. Paraoxonase 1 is much the most extensively researched and strategies will hopefully emerge to increase its activity and provide a more satisfactory test of the antioxidant hypothesis of atherosclerosis than antioxidant vitamins have done.
Mackness
Bharti
B
University Department of Medicine, Manchester Royal Infirmary, UK. bmack@central.cmht.nwest.nhs.uk
Durrington
Paul N
PN
Mackness
Michael I
MI
D001161:Arteriosclerosis / Q000201:enzymology / Q000235:genetics; D043303:Aryldialkylphosphatase; D003327:Coronary Disease / Q000201:enzymology* / Q000235:genetics*; D004950:Esterases / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D009747:Nutritional Physiological Phenomena
D004950:Esterases; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human