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Oxidative Stress
Joe M. McCord, PhD
The superoxide free radical has come to occupy an amazingly
central role in a wide variety of diseases. Our metabolic focus on
aerobic energy metabolism in all cell types, coupled with some
chemical peculiarities of the oxygen molecule itself, contribute
to the phenomenon. Superoxide is not, as we once thought, just
a toxic but unavoidable byproduct of oxygen metabolism.
A REDOX PRIMER
At the risk of inducing unpleasant flashbacks to college
chemistry courses, let us consider the class of chemical
reactions upon which our bodies rely for energy producFrom Webb-Waring Institute, University of Colorado Health Sciences
Center, Denver, Colorado.
Correspondence should be addressed to Joe M. McCord, PhD, Box
C-321, University of Colorado, 4200 East Ninth Avenue, Denver, Colorado 80262.
652
Figure 1. A schematic representation of signal transduction pathways for superoxide radical. Mitochondrial respiration accounts for
most of the superoxide generated in a cell with leakage sites at Complex I and at ubisemiquinone. The steady-state concentration of
superoxide is kept low in all compartments by SODs, not shown. The low levels of the radical remaining may modulate various
kinases, or may activate transcription factors directly to effect gene regulation in the nucleus. It is interesting to speculate on the
existence of a cell surface receptor for superoxide (R), which might transduce various responses within the cell by means of kinase
activation, for example. There is presently no direct evidence for such a receptor.
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They can reduce lipid peroxides as well as hydrogen peroxide and are very important enzymes in the prevention
of lipid peroxidation to maintain the structure and function of biologic membranes.
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ried, and interpreted, especially by the cells genetic machinery. The study of redox regulation of gene expression
has exploded in recent years and clearly suggests that oxidants are major determinants of gene expression. Reactive oxygen intermediates have been implicated in the
activation of a variety of kinases [such as the Src kinase
family (32); protein kinase C (33); mitogen-activated
protein kinase, MAPK (34); and receptor tyrosine kinases
(35)] and transcriptional factors, such as AP-1 and
NF-B (34,36). An additional layer of complexity is offered by oxidant modification of redox-sensitive proteins, such as thioredoxin (37,38), which can regulate the
activity of certain stress kinases (39). Figure 1 depicts a
schematic representation of how reactive oxygen species
may regulate gene expression. This extensive interface between oxidants and reductants and the cells genetic machinery results in responsiveness to exogenous oxidant
exposure and to remarkably effective mechanisms governing redox homeostasis under normal conditions. The
unfolding complexity of the system further suggests just
how badly things can go wrong when a cells redox status
is upset.
cific roles for free radicals and oxidative stress in a number of the diseases mentioned above.
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