From the Pulmonary-Critical Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892
The role in "normal" aging of
oxidative damage to cellular components, as well as its part in the
morbidity associated with many age-related diseases, has been
increasingly recognized and investigated in recent years. Although the
concept developed only slowly over several decades, it seems now widely
accepted that an important element in normal and premature aging
processes, as well as in certain degenerative diseases, is the
accumulation of proteins, and DNA and lipids, that have been damaged by
oxygen radicals or other reactive oxygen species and no longer function normally. As damaged molecules accumulate, they can contribute to the
increasingly inefficient removal of newly generated oxidized products,
i.e. a disequilibrium that is self-perpetuated, even autoaccelerated.
These consequences of life in an aerobic environment are counteracted
(prevented, repaired, or ameliorated) by numerous biochemical reactions
and the enzymes that catalyze them, which have perhaps, to some extent
at least, evolved for this purpose. Despite an incomplete understanding
of the complex molecular mechanisms that underlie oxidative damage and
its reversal or prevention, this appears to be an appropriate time for
assessment of the current state of this problem by scientists who have
made major contributions, both experimental and conceptual, to its
definition and solution.
The series of Minireviews on "Oxidative Modification of
Macromolecules" begins in this issue with a contribution from Irwin Fridovich entitled "Superoxide Anion Radical (O In the second Minireview of the series, entitled "Formation,
Prevention, and Repair of DNA Damage by Iron/Hydrogen Peroxide," Ernst S. Henle and Stuart Linn provide an excellent overview and summary of the numerous biochemical reactions that produce reactive oxygen species. Emphasis is on the role of iron-mediated Fenton reactions in DNA damage and its repair. The overall consideration of
related cellular reactions involved in removal of oxidizing molecules
and restoration or elimination of damaged DNA is valuable also as a
basis and background for the other reviews.
The DNA story continues with "Oxidative Decay of DNA" by Kenneth B. Beckman and Bruce N. Ames. The latter author has been an international
leader in the field of mutagenesis and genetic toxicology for 25 years.
Among his major contributions is the early introduction of methods for
measuring oxidative damage, including ways to isolate from urine and
quantify products of DNA damage that are excised during repair. Of
these, thymine glycol and 8-hydroxy-2-deoxyguanosine are now accepted
as a standard measure of oxidative modification of DNA.
"Protein Oxidation in Aging, Disease, and Oxidative Stress" by
Barbara S. Berlett and Earl R. Stadtman extends consideration of
the subject to the diverse and specialized chemistry as well as
the effects of oxidative modification of individual amino acids. Stadtman and his associates over several years have demonstrated site-specific oxidative modifications of susceptible proteins that
destroy catalytic or structural function. They have elucidated the
chemical mechanisms of many of these amino acid-damaging reactions. They have also established clear relationships between the
effects of these reactions in an experimental setting and the
properties of damaged proteins accumulated in tissues of aging
animals.
In the last Minireview of the series, Daniel Steinberg addresses
specifically "Low Density Lipoprotein Oxidation and Its
Pathobiological Significance." This is a subject that Steinberg has
pursued avidly since the early 1980s. He was among the first to
recognize and begin systematically to investigate the biochemistry and
pathological significance of oxidatively modified low density
lipoprotein (LDL), which is now the subject of widespread interest
vis à vis its role in the etiology of
atherosclerosis.
Although five Minireviews could not pretend to present a comprehensive
summary of the "state of the field" in 1997, it is hoped that the
series will convey a sense of the importance, implications, and growing
interest in the mechanisms of the oxidative reactions, ways in which
they may be prevented or reversed, and failing those alternatives, how
the products may be eliminated or repaired. It is notable that although
each Minireview is focused on a different topic, one common theme that
emerges is the importance of redox cycling of transition metals,
especially iron.
Identification and quantification of the products of oxidative
modification of DNA, proteins, and lipoproteins will enable investigators to define more precisely the types of damage that are
found in aging, atherosclerosis, arthritis, and numerous
"degenerative" diseases. Knowledge of the chemistry and enzymology
of the processes involved in the generation as well as the
amelioration of oxidative damage is a necessary basis for rational
preventive or therapeutic interventions.
2),
Superoxide Dismutases, and Related Matters." Fridovich was the first
to show that the superoxide anion radical is a product of numerous
enzyme-catalyzed reactions as well as of the "autoxidation" of many
drugs and metabolites. He established that superoxide is produced
during autoxidation of epinephrine and ferredoxins as well as in
reactions catalyzed by xanthine oxidase. Most importantly, he
discovered that the injurious effects of the superoxide anion radical
are prevented physiologically by the action of a family of superoxide
dismutases, which are now recognized as critical components of the
antioxidant defense system. Because the subject has become so broad,
this Minireview is limited to bringing up to date specific aspects that
are of particular interest to the author.
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