Oxidative Stress: Defense or Disease

Abundant research has demonstrated that reactive oxygen species (ROS) are formed in the human body. They contribute to our defenses, as well as cause oxidative damage to DNA, block cellular signal transduction, and modulate gene expression and enzyme activity (Wiseman and Halliwell, 1996). The possibility that ROS contribute to the etiology of cancer, cardiovascular disease, and neurodegenerative processes has been an area of increasing inquiry, investigation, and controversy.

ROS is a collective term that includes oxygen and non-oxygen radicals. These biological species include superoxide (O₂•–), hydroxyl (OH•), peroxyl (RO₂ •), alkoxyl (RO•), and nitric oxide (NO₂) derived products. If ROS induce oxidative stress, then therapeutic intervention could include antioxidants.

Plants are natural sources of many antioxidants. After all, photosynthesis leads to an oxygen-rich environment, and these antioxidants may protect the plants from oxidative damage. The intriguing question is whether these plant-derived antioxidants protect humans from oxidative damage.

From our basic understanding of redox biology, we know that animals, including humans, have several ROS synthesis and scavenging mechanisms through which the body maintains a critical balance of ROS for defense purposes. These mechanisms are well known and readily assessed, but what in-vivo tools are available to evaluate clinically relevant antioxidant efficacy?

Many chemical methods assess in-vitro antioxidant activity. They include oxygen radical absorbance capacity (ORAC), total radical-trapping antioxidant parameter (TRAP), Trolox equivalent antioxidant capacity (TEAC), and peroxyl radical scavenging capacity (PSC). However, none of them addresses the distribution, absorption, metabolism, and excretion (DAME) of the purported antioxidant substances.

Cellular antioxidant activity (CAA) is a more biologically relevant assessment of antioxidant activity (Wolfe and Liu, 2007). This assay accounts for some aspects of DAME parameters, and may be applicable to screening substances or extracts for their antioxidant potential. Its complexity, however, precludes its use as a rapid quality control tool for clinical assessment.

It is interesting to note that many large-scale clinical studies with antioxidants have failed to demonstrate a reduced risk of specific diseases. Beta-carotene, vitamin E, vitamin A, vitamin C, and selenium are the most notable antioxidants of those studied.

In a recent meta-analysis of 68 trials of various designs, these antioxidants were consumed for 3 months to 10 years by healthy adult subjects and individuals with pre-existing conditions (Bjelakovic et al., 2007). Those conditions included cardiovascular disease, dyslipidemia, diabetes, some forms of cancer, Alzheimer’s disease, and smoking. An array of non-specific clinical outcomes was determined to assess efficacy and relative risk of mortality.

The analysis indicated that none of the antioxidant interventions presented a beneficial effect and suggested that beta-carotene, vitamin A, and vitamin E supplementation in these studies increased the risk of mortality.

In-vitro data from flavonoids and other polyphenols are equally intriguing, as we examine foods and food components for their potential health benefits. Several epidemiological studies suggest that flavonoids, such as those in red wine and cocoa, may be cardioprotective. Considering the low bioavailability of these compounds, the numerous biotransformations that occur due to gastrointestinal tract microflora, and the potential complexities of their non-antioxidant actions within biological systems, one may speculate that these antioxidants might be more effective in the stomach and proximal and/or distal bowel than peripheral tissues.

Fruits and vegetables are full of antioxidants. The complex matrix of food with its spectrum of naturally occurring and likely synergistic ROS scavengers, such as flavonoids, lycopene, selenium, and resveratrol, continues to be consistently linked with reduced risks for pathology.

The specific interplay between naturally arrayed antioxidants and our particular molecular genetics may be a far more powerful paradigm guiding the development of functional foods than the comparatively simplistic, pharma-like notion of supplementation via nutraceuticals of varying forms and doses.

The importance of developing robust bioanalytical tools, studying whole foods, and considering the totality of the evidence with well-defined mechanisms and clinically relevant outcomes cannot be understated.

References for the above studies are available from the authors.

by Roger Clemens, Dr.P.H.,
Contributing Editor
Special Projects Advisor,
ETHorn, La Mirada, Calif.
[email protected]

by Peter Pressman, M.D.,
Contributing Editor
Attending Staff, Internal Medicine,
Cedars-Sinai Medical Center,
Los Angeles, Calif.
[email protected]