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Antioxidants to abrogate free radicals: new insights to challenge currently held beliefs.

Introduction

Antioxidant supplements are among the most popular health products in the world and one of the highest selling items without the requirement of a prescription. (1) The reason for this influx of market value is largely due to in vitro research conducted on free radicals and the suggested benefits from antioxidant compounds in abrogating the over-production of free radicals. There has been a plethora of investigations on antioxidants and the rescuing of the purported oxidative damage to macromolecules that ensues. The conclusions emanating from in vitro and in vivo experimental models have no relevance to normal physiological function and therefore no relevance to the risk of developing a chronic disease or affecting the aging process. (2) Hydrogen peroxide is the stand out substance employed in such investigations, with thousands of articles in the medical and scientific literature reporting it as causal for macromolecular damage and severe cellular toxicity. The demonstration of cellular toxicity is based on employing hydrogen peroxide levels that far exceed those observed under normal physiological conditions, otherwise it is cited that at lower levels the phenomenon is not detectable. (3) The hypothesis that justifies this phenomenon is that the high levels of hydrogen peroxide are requisite in order to demonstrate the toxic effect that hydrogen peroxide has on cells. Additional experiments investigating the levels of cellular catalase and glutathione peroxidase, which function to regulate the level of hydrogen peroxide, further postulate that these enzyme systems prevent the cellular damage that hydrogen peroxide may cause. In contrast to this, hydrogen peroxide is not a toxic compound at physiological levels. (4)

The human metabolome is an expression of a finely tuned dynamic equilibrium which is comprised of thousands of anabolic and catabolic reactions, and all cellular systems are finely regulated. However, there is no perfect machine and malfunctions can occur. (4) If there is a small inappropriate leakage of 'free radicals', the mitochondria or cell can be damaged and will go into apoptosis (cell death) and cannot continue to function in a compromised state as suggested by some authors. (5,6) Currently, there are no blinded human clinical trials establishing excessive systemic over-production of reactive oxygen species as the primary cause of aging or associated diseases. (4)

Commentary

Recently, the antioxidant-free radical theory of chronic disease and aging has been challenged. (4) It has been posited that an industry has been built on the proposition that it is essential to prevent oxidative damage by administering small molecules designated as antioxidants for the amelioration of the aging process and treatment of chronic diseases. However there is no compelling evidence from human clinical trials to support this contention. (4,7,8)

Harman (9) in 1956 hypothesized that free radical production (oxygen radical formation) was a major deleterious contributor to the aging process and degenerative disease due to its attack on cell constituents (macromolecules such as DNA and proteins) and connective tissue. The hypothesis that free radicals were causal for oxidative damage received strong support from an extensive set of experiments. Boveris and Chance (10) in 1973 demonstrated that large amounts of superoxide anions were generated by the mitochondrial electron transport chain during the oxidative phosphorylation phase of the Kreb's cycle, whereby complex I and II reduced coenzyme [Q.sub.10] and its oxidation by complex III. Chance et al., (11) in 1979, then estimated that 1-3% of inspired oxygen was converted to reactive oxygen species (ROS), which would indeed be toxic to cells. Chance's experiments, however, were contradicted when Staniek and Nohl (12) (2000) and St-Pierre et al., (13) (2002) demonstrated that intact normally respiring mitochondria do not produce high concentrations of ROS and that the earlier extrapolations of superoxide anion and hydrogen peroxide were over-estimated by several orders of magnitude. Therefore, the high amounts of ROS were not produced in physiologically normally respiring human mitochondria and that the human cellular metabolome tightly regulates the production of ROS/RNS. This indicated that oxidative damage did not occur unless the system was induced to do so in a non-physiological environment.

In a recent review by Tobe (14) (2013), investigations on mitochondrial dysfunction and oxidative damage in major depressive disorder were discussed. The human studies described were based on brain imaging captured via magnetic resonance imaging (MRI) and post mortem histologic studies. Tobe (14) suggested that the decreased size of the brain, decreased glial cell density and neuronal size linked with major depressive disorder, biopolar or schizophrenia were due to oxidative stress. There was no scientific or mechanistic explanation that confirmed this suggestion. The basis of the discussion was cited to animal studies, which had established a non-physiological environment that was causal for increased ROS production, inhibition of mitochondrial respiration and oxidative DNA damage. (15-17) Such investigations reinforce and reiterate that oxidative damage does not occur under normal physiological conditions The cellular damage alluded to in these investigations occurs in a set of experiments with induced abnormal productions of ROS/RNS.

Additional recent experiments by Villanueva and Kross (18) have questioned the role of antioxidant supplementation, suggesting a hypothesis that supplementation of antioxidants may cause antioxidant-induced stress whereby antioxidants overwhelm the body's free radical production. Many investigators report benefits of antioxidant administration; however, there are only a few that question the possible harmful effects. (18)

Free radicals have been designated as largely harmful and thus having a negative impact on cellular metabolism and mitochondria, and being causal for macromolecular oxidative damage. (19) It is posited that ROS and RNS participate in specific functions and play an important role in signal transduction in many physiological events. For example, ROS and RNS play a significant role in signal transduction of cytokine receptors, tyrosine receptors, serine/threonine kinases, G protein-coupled receptors, ion-channel linked receptors in response to angiotension II, cytokines, glutamate, epidermal growth factor, vascular endothelial growth factor, tumour necrosis factor a and platelet derived growth factor. (18,19) Furthermore, hydrogen peroxide is a known mitogen. (4)

Villanueva and Kross (18) (2012) form the argument that excess consumption of administered antioxidants can overwhelm the cellular function of ROS/RNS and therefore decrease their biological function within cells. This deleterious action then goes on to interfere with the normal cellular processes by disrupting biochemical and physiological activity required for normal cellular function. They list nine trials indicating no effect from antioxidant supplementation and six trials that found harmful effects from antioxidant supplementation versus twelve that report benefit. (18) This body of evidence then raises the query as to antioxidant supplementation benefits versus safety.

The question may not only be if antioxidant supplementation is beneficial or detrimental but whether there is an antioxidant effect. What has been found is that antioxidants referred to in the literature are also pro-oxidants, inducing the formation of hydrogen peroxide, a necessary biochemical requisite for optimal cellular function. It would hence seem that antioxidants may promote healthy cellular metabolism by providing an oxido-reductase action.

An example of this is coenzyme Q10, which is a key component in the oxidative phosphorylation section of energy production and electron transport chain as well as other organelle oxido-reductase activity. (4) Coenzyme Q10 has been labelled as a strict antioxidant; however, it also has a pro-oxidant function through the formation of superoxide anion and hydrogen peroxide that is a major factor in its beneficial mode of activity. (8)

Conclusion

The canon belief that the production of ROS and RNS leads to random deleterious modification of macromolecular species, mitochondria and cellular metabolism, and that oxidative damage is a major contributor to aging and related systemic diseases is untenable. Furthermore, the administration of antioxidants such as vitamin A, C, E, compounds found in herbs or coenzyme Q10 that can ameliorate oxidative stress is flawed. ROS and RNS are products of normal cellular metabolism and are necessary for normal physiological functioning of the organism. This process is tightly regulated by hormones, cytokines and other mechanisms. Antioxidants can also act as pro-oxidants (e.g. ascorbate), therefore readdressing the action of these molecules to oxido-reductase molecules may serve researchers with a more appropriate mode of action for further investigations of efficacy.

The antioxidant compounds marketed still play a vital role and should be included in a prescription of health. Further clinically relevant research is required that takes into consideration that the evolutionary progression of humans has become dependent upon the production of ROS and RNS. Reassessment of the antioxidant theory and a new paradigm of thinking are certainly required.

References

(1.) Choices. 2011. Supplements who needs them? NHS. June: 1-33.

(2.) Linnane AW. 2010. My life as a biochemist and molecular biologist. IUBMB Life. 62(7):527-30.

(3.) Saeidnia S, Abdollahi M. 2013. Toxicological and pharmacological concerns on oxidative stress and related diseases. Toxicol Appl Pharmacol. In press: doi: 10.1016/j.taap.2013.09.031.

(4.) Linnane AW, Kios M, Vitetta L. 2007. Healthy aging: Regulation of the metabolome by cellular redox modulation and prooxidant signaling systems: The essential roles of superoxide anion and hydrogen peroxide. Biogerontology 8(5): 445-467.

(5.) Parikh SM. 2013. Therapeutic targeting of the mitochondrial dysfunction in septic acute kidney injury. Curr Opin Crit Care In Press: DOI:10.1097/MCC.0000000000000038

(6.) Muyderman H, Chen.T. 2013. Mitochondrial dysfunction in ALS --a valid pharmacological target? Br J Pharmacol In Press: doi: 10.1111/bph.12476.

(7.) Linnane AW, M. Kios, Vitetta L. 2007. The essential requirement for superoxide radical and nitric oxide formation for normal physiological function and healthy aging. Mitochondrion 7(1-2):1-5.

(8.) Linnane AW, Kios M, Vitetta L. 2007. Coenzyme Q(10)--its role as a prooxidant in the formation of superoxide anion/hydrogen peroxide and the regulation of the metabolom. Mitochondrion 7:S51-61.

(9.) Harman D. 1956. Aging: a theory based on free radical and radiation chemistry. J Gerontol 11(3):298-300.

(10.) Boveris A, Chance B. 1973. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 134(3):707-16.

(11.) Chance B, Sies H, Boveris A. 1979. Hydroperoxide metabolism in mammalian organs. Physiol Rev 59(3):527-605.

(12.) Staniek K, Nohl H. 2000. Are mitochondria a permanent source of reactive oxygen species? Biochim Biophys Acta 460(2-3):268-75.

(13.) St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD. 2002. Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 277(47):44784-90.

(14.) Tobe EH. 2013. Mitochondrial dysfunction, oxidative stress, and major depressive disorder. Neuropsychiatr Dis Treat 9:567-73.

(15.) Lee HM, Reed J, Greeley GH Jr, Englander EW. 2009. Impaired mitochondrial respiration and protein nitration in the rat hippocampus after acute inhalation of combustion smoke. Toxicol Appl Pharmacol 235(2):208-15.

(16.) Lee HM, Greeley GH, Herndon DN, Sinha M, Luxon BA, Englander EW. 2005. A rat model of smoke inhalation injury: influence of combustion smoke on gene expression in the brain. Toxicol Appl Pharmacol 208(3):255-65.

(17.) Lee HM, Greeley GH Jr., Englander EW. 2011. Transgenic overexpression of neuroglobin attenuates formation of smoke-inhalation-induced oxidative DNA damage, in vivo, in the mouse brain. Free Radic Biol Med 51(12):2281-7.

(18.) Villanueva C, Kross R. 2012. Antioxidant-induced stress. Int J Mol Sci 13(2): 2091-109.

(19.) Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. 2007. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39(1):44-84.

Janet M Schloss [1], Luis Vitetta [1,2]

[1] The University of Queensland, School of Medicine, Level 5, TRI, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Australia 4102.

[2] Medlab, Sydney, Australia 2015.

Correspondence:

Ms Janet Schloss, The University of Queensland, School of Medicine.

Level 5, TRI, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland, Australia 4102

Email: janet.schloss@uqconnect.edu.au
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Title Annotation:Commentary
Author:Schloss, Janet M.; Vitetta, Luis
Publication:Australian Journal of Herbal Medicine
Article Type:Report
Geographic Code:8AUST
Date:Mar 1, 2014
Words:1942
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