Twenty-first century phox: not yet ready for widespread screening.

Abstract

Unstable forms of oxygen are highly reactive and have been widely implicated in disease pathogenesis. Indeed, interest in detecting their formation extends beyond this planet.1 Given their intrinsic evanescence, the generation of reactive oxygen species (ROS) in vivo has been inferred by the quantitation of products of their reaction with lipids,2 proteins,3 and DNA.4 Such data have implicated ROS in cardiovascular diseases such as atherosclerosis5 6 7 8 and ischemia-reperfusion syndromes.9 10 Evidence consistent with increased ROS generation based on such methodology has emerged in individuals with cardiovascular risk factors such as hypercholesterolemia,11 12 cigarette smoking,13 14 and alcoholism.15 Despite this, the outcome of trials of antioxidants as protective agents in cardiovascular diseases have been contradictory.16 17 18 However, a limitation of these trials is that none of them have included an assessment of ROS generation, either as an entry criterion or as a basis for dose selection. As in model systems in vitro,19 the response of humans to exogenous antioxidants is highly conditioned by the extent to which endogenous antioxidant defenses are depleted.20 21 Thus, inclusion of phenotypically inappropriate patients in such trials may have undermined sample size calculations and, consequently, the basis of statistical inference. If the functional competence of the diverse enzymes that comprise our defense against ROS is a critical determinant of our capacity to respond to exogenous antioxidants, genetic variations in the activity or expression of such enzymes may contribute to interindividual differences in susceptibility to ROS-mediated diseases. Reduced activity of the superoxide dismutase expressed in endothelial cells has been reported in patients with coronary artery disease (CAD) and correlates with their degree of endothelial dysfunction.22 Similarly, serum levels of paraoxonase (PON) 1, an enzyme that protects low density lipoprotein from oxidative …