Roger Clemens

The potential health benefits of natural antioxidants, while interesting, seem to escape our basic understanding of biological oxidation processes. Oxidation balances both very beneficial, even crucial, outcomes with decidedly negative impacts. This suggests that moderation in the use of some antioxidants may be advisable.Yet let us not forget that a large measure of the biological oxidation that occurs in the body is essential for extracting energy from food and is highly adaptive, depending on health status.

Apart from energetics, oxidation supports immunological integrity. Phagocytes, our mobile white blood cells, kill encapsulated microbes through oxidative cleavage of surface carbohydrates, releasing glycan fragments and microbial contents that serve as ligands for immune receptors, which in turn tailor the immune response against the pathogen. This beneficial oxidative process does have a downside: In addition to energy, it results in the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These compounds, such as hydrogen peroxide (an ROS) and nitric acid (an RNS), produce “oxidative stress” (Halliwell, 1996). There is growing evidence of a causal association of oxidative stress and human pathology (Gutteridge and Halliwell, 2010). Several antioxidant studies failed or were terminated early due to unexpected negative impact on intervention groups. For example, ROS may not be important in some diseases, such as myocardial infarction, and among individuals with advanced pathology, such as smokers with pulmonary insufficiency, where intervention may be too late for therapeutic or even prophylactic application. It is difficult to ascribe long-term health benefits of individual components. This position, therefore, emphasizes the importance of whole foods and the composite of compounds found in these foods. Remember, while some of these compounds may be beneficial, some of the natural compounds in foods are also natural toxicants.

A recent report from the Institute of Medicine outlined numerous criteria for appropriate biomarkers of health and disease. With respect to biomarkers of oxidative stress, technical criteria and issues have been outlined (Halliwell, 2009). However, there is a lack of validation of proposed clinical biomarkers or even total antioxidant capacity (usually in vitro assessments). Yet many clinical studies suggest these and other surrogate markers of antioxidant status or cellular damage, such as flow-mediated dilatation and high sensitive C-reactive protein, may be useful in describing valuable outcomes such as blood pressure and inflammation relative to dietary components and health (Berry et al., 2010; Franzini et al., 2010).

The concentration and types of polyphenols in foods measured by popular antioxidant capacity assessments are inconsistent. Yet the ROS scavenging potential of dietary oxidants, particularly those found in fruits and vegetables, has been demonstrated in vitro. For example, the 1992“French paradox” report, subsequent description of health benefit mechanisms, and additional epidemiological data indicate further research is warranted (Renaud and de Lorgeril, 1992; Howitz et al., 2003; Ghanim et al., 2010).

On the other hand, there are data that some antioxidants may be pro-oxidants. Polyphenols typically oxidize during thermal processing (Akagawa et al., 2003). Polyphenols are also subject to oxidation in culture media, which leads to the production of ROS and potential cytotoxic environments (Long et al., 2000). In addition, polyphenols and their oxidant metabolites are metabolized as xenobiotics through hepatic cytochrome P450 glucoronidation and sulfation pathways (Halliwell, 2007).

It was recently noted that the dose and length of exposure to some antioxidants, such as resveratrol, may be critical in assessing the benefits. A recent report indicated different effects of androgen-responsive human prostate cancer cells when in vitro and in vivo (Wang et al., 2008). These investigators also demonstrated small amounts of resveratrol can increase angiogenesis and inhibit apoptosis in xenograft studies, which counter efforts to reduce cancer risk. Importantly, these kinds of responses depended upon the line of prostate cancer cells, the phytonutrients, the genetic profile of the disease, cell receptor and cell signaling functions, and other variables.

While the bulk of epidemiological evidence supports the nutritional/health value of fruits and vegetables, the doses of individual components they contain, such as specific antioxidants that may contribute to improved health and reduced risk of certain diseases, remain uncertain.

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

Peter Pressman, M.D.,
Contributing Editor
LCDR, Medical Corps, U.S. Navy,
Director Expeditionary Medicine,
Task Force for Business & Stability Operations 
[email protected]


Akagawa, M., Shigemitsu, T., and Suyama, K. 2003. Production of hydrogen peroxide by polyphenols and polyphenol-rich beverages under quasi-physiological conditions. Biosci. Biotechnol. Biochem. 67(12): 2632-40.

Berry, N., Davison, K., Coates, A.M., Buckley, J.D., and Howe, P.R.C. 2010. Impact of cocoa flavanol consumption on blood pressure responsiveness to exercise. Br. J. Nutr. 103(10): 1480-84.
Franzini, L., Ardigò, D., Valtueña, S., Pellegrini, N., Del Rio, D., Bianchi, M.A., Scazzina, F., Piatti, P.M., Brighenti, F.I., and Zavaroni, I. 2010. Food selection based on high total antioxidant capacity improves endothelial function in a low cardiovascular risk population. Nutr. Metab. Cardiovasc. Dis.  doi:10.1016/j.numecd.2010.04.001.

Ghanim, H., Sia, C.L., Abuaysheh, S., Korzeniewski, K., Patnaik, P., Marumganti, A., Chaudhuri, A., and Dandona, P. 2010. An anti-inflammatory and reactive oxygen species suppressive effects of an extract of Polygonum cuspidatum containing resveratrol. Clin. Endocrinol. Metab. 95(9): E1-8.

Gutteridge, J.M. and Halliwell, B. 2010. Antioxidants: Molecules, medicines, and myths. Biochem. Biophys. Res. Comm. 393(4): 561-64.

Halliwell, B. 1996. Antioxidants in human health and disease. Annu. Rev. Nutr. 16: 33-50.

Halliwell, B. 2007. Dietary polyphenols: Good, bad, or indifferent for your health. Cardiovasc. Res. 73(2): 341-47.
Halliwell, B. 2009. The wanderings of a free radical. Free. Rad. Biol. Med. 46: 531-42. 

Howitz, K.T., Bitterman, K.J., Cohen, H.Y., Lamming, D.W., Lavu, S., Wood, J.G., Zipkin, R.E., Chung, P., Kisielewski, A., and Zhang, L.L. 2003. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425: 191-96.

Long, L.H., Clement, M.V., and Halliwell, B. 2000. Artifacts in cell culture: rapid generation of hydrogen peroxide on addition of (-)-epigallocatechin, (-)-epigallocatechin gallate, (+)-catechin, and quercetin to commonly used cell culture media. Biochem. Biphysiol. Res. Comm. 273(1): 50-53. 

Renaud, S. and de Lorgeril, M. 1992. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339: 1523-26.

Wang, T.Y., Hudson, T.S., Wang, T.-C., Remsberg, C.M., Davies, N.M., Takahashi, Y., Kim, Y.S., Seifried, H., Vinyard, B.T., Perkins, S.N., and Hursting, S.D. 2008. Differential effects of resveratrol on androgen-responsive LNCaP human prostate cancer cells in vitro and in vivo. Carcinogenesis 29: 2001-10.