Redox medicine – the double-edged sword of oxidants

You may have read the packaging on an item at the grocery store and seen the words “High in Antioxidants” shining out. Antioxidants must be important then – why else advertise it? If antioxidants are good, then oxidants must be the opposite. So, what’s the deal with oxidation?

The biology of oxidants is a topic of interest in many subspecialities of science – ranging from free radical chemistry to cancer biology. In order to understand these molecules, it is important to establish some terminology:

Now that we’ve clarified some terms, we can look at oxidants on a physiological level. Oxidants are formed from biological process including during normal metabolism. In the mitochondria, oxidative phosphorylation is the transfer of electrons in a baton-relay race that ends with the final electron acceptor, (the final oxidant), H₂O. Normal chemical kinetics sometimes result in H₂O being further reduced into reactive oxygen species (ROS) such as superoxide (O₂^–) or hydrogen peroxide (H₂O₂), the former of which is also a free radical. ROS can continue to propagate and become free radicals that interact with and modify lipids, proteins and most dangerously, DNA. While there are homeostatic counter molecules, antioxidants, there are instances where the levels of oxidants greatly exceed those of antioxidants and results in a state of biological oxidative stress. The effect of oxidative stress is oxidative damage to the essential macromolecules.

Oxidative damage can have beneficial uses and detrimental effects. During immune responses against virus-infected cells or bacteria, phagocytes cells engulf pathogens into a phagocytic vacuoles where they are met with a oxidative burst, an onslaught of peroxides, superoxides and other oxidants meant to destroy the pathogen. In this scenario, cells have harnessed the destructive power of oxidants in a controlled and contained manner as an immune line of defense.

In contrast, the unchecked accumulation of oxidant species can lead to devastating damage. This can occur in a number of ways.

1. External sources of oxidants. The most notable exogenous source of oxidants is cigarette smoke, which introduces considerable oxidative stress and damage to DNA.
2. Dysregulation of homeostatic checks. When enzymes that control oxidant levels develop mutations, the delicate oxidant and antioxidant balance can be skewed towards a pro-oxidant state.
3. Antioxidant deficiency. Without the counter-defense of antioxidant molecules and the enzymes that generate them, ROS propagation can go forward unchecked.

A pro-oxidant state has trickle-down effects that are implicated in a multitude of illnesses including cardiovascular, neurological, respiratory, and ocular diseases (ref) as well as multi-organ cancers. A simple example of disease development is in atherosclerosis where oxidation of lipids in a process called lipid peroxidation contributes to plaque formation.

Thus emerges the field of redox medicine, which aims to harness and reinforce the antioxidant defense system.

Dietary antioxidants

The sharp edge: dietary antioxidants such as vitamin C from fruits and green vegetables, vitamin E from whole grains and nuts, beta-carotene from squash and carrots and lycopene from tomatoes can neutralize oxidative stress.

The other sharp edge: these same powerful antioxidants can overshoot their effects and lead to the propagation of metal ion radicals, which can circle back to the pro-oxidative state. In addition, certain antioxidants, such as lycopene from tomatoes, can have negative effects in excess.

Exercise

The sharp edge: While moderate exercise is known to produce oxidants, these levels are usually low enough to be scavenged by homeostatic means. In fact, exercise-induced pro-oxidant production can trigger a stronger antioxidant defense than immediately required, thus keeping the system armed and ready.

The other edge: The deleterious effects of exercise arise when the exercise is overly exhaustive and combined with a diet enriched in fats and carbohydrates and limited in antioxidant nutrients. The sum of excess oxidants and excess targets for oxidation leads to a state of oxidative stress. Recall the atherosclerosis plaques?

In Cancer

Based on our understanding of oxidative stress, it should be no surprise that oxidative damage can contribute to cancer pathology. DNA damage that accumulates, is transcribed, and then translated leads to aberrant macromolecules that affect signalling and physiology. It then follows that pharmaceutically moving the balance towards an antioxidant state can be useful. Targeting enzymes that generate oxidants or enhancing the antioxidant systems is the mantra of many therapeutics.

Conversely, some cells known as cancer stem cells, are known to have lower levels of ROS, thus making them resistant to antioxidant treatment. In fact, in some instances, lower levels of ROS act a protection against peroxide induced apoptosis. In this way, cancer cells mask themselves using the other side of the redox equation.

This double edge sword is a prime example of a core principle in chemistry, biology, and health; the need for moderation and a middle-ground. The struggle to establish it is evident in the need for physiological homeostasis and accepting trade-offs in medicine. It is no surprise then, that the maintaining the equilibrium of the redox equation is a delicate a balancing act.

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References

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3454471/#:~:text=Reactive%20oxygen%20species%20(ROS)%20are,mount%20an%20effective%20antioxidant%20response.

https://link-springer-com.myaccess.library.utoronto.ca/content/pdf/10.1007/164_2020_380

https://librarysearch.library.utoronto.ca/discovery/search?query=any,contains,Oxidants%20in%20Physiological%20Processes&tab=Everything&search_scope=UTL_AND_CI&vid=01UTORONTO_INST:UTORONTO&offset=0

https://www.pnas.org/doi/epdf/10.1073/pnas.90.17.7915

https://onlinelibrary.wiley.com/doi/abs/10.1111/jfbc.13145

https://journals-scholarsportal-info.myaccess.library.utoronto.ca/pdf/01458884/v44i0003/na_uoaactwnp.xml_en

https://www.cbhs.com.au/mind-and-body/blog/Antioxidant-supplements-do-you-need-them