Oxidative stress, Reactive oxygen species

Ask Dr. J

Does the Dose Really Make the Poison?

By Jim Cross, ND

Was Paracelsus correct with his statement above from the 16^th century¹? Making sense of this statement goes a long way into helping us understand how we can effectively deal clinically with the garbage bag of chemicals and heavy metals that we are assaulted with in the 21^st century plus what is still present from the 20^th century.

Cat Stevens’ wonderful song, “On the Road to Find Out,” contains a line that has always helped me make sense of seemingly disparate, contradictory options: “I found my head one day when I wasn’t even trying.” Like most readers and practitioners of the Townsend, I have gone through multiple health incarnations in this lifetime: taking large doses of multivitamins/minerals because the soil is depleted, being a vegetarian because meat is too acidic for our bodies, taking tons of antioxidants because the environment is just too toxic, etc., etc. Fortunately, I am not satisfied with the status quo and continue to read, attend seminars, and learn from my patients. Because of this, I continually modify what I eat and take as supplements and also adjust what I recommend to my patients. I no longer am a vegetarian and buy fresh, local mostly organic fruits and veggies which, I feel, provide me with more than adequate nutrition. I have also begun to question “the world is just too toxic” argument and thus we need to consume tons of antioxidants. Fortunately, as the line from the song above so elegantly states, I keep moving in new directions even though I don’t necessarily push myself to. My drive for perfection makes sure that these opportunities keep appearing in my life, and my being is open enough to recognize the importance of these new directions.

Our cells generate supposed dastardly molecules called reactive oxygen species/ROS naturally during mitochondrial oxidative metabolism but also in response to molecular invaders from our environment such as heavy metals, pesticides, volatile organic compounds, etc. If these ROS are not neutralized, they have the ability to overwhelm cellular defense strategies and initiate cellular damage that can lead to various disease states like coronary artery disease, cancer, neurodegenerative diseases, and just plain old aging. Conflicting studies are beginning to show that these same evil ROS molecules can actually serve as critical signaling molecules for healthy cell survival through regulating proliferative and apoptotic pathways.²

So, what path is one to follow: spend hundreds of dollars on effective ROS quenchers or walk down a San Francisco street and deeply breath the polluted air that exists there? As my father so astutely taught me, the answer always appears to lie in the middle of the road. I know this is hard to swallow for Trump/Hillary supporters because unfortunately the squeaky wheel always seems to get the grease. I do think, though, my father had the right idea: be quiet and observe what is really happening and don’t let anyone dissuade you from your path.

Although some data suggests that high levels of ROS contribute to insulin resistance, there are other datasets that suggest the complete opposite might be true. For instance, there is some evidence that mitochondrial oxidants are required for the glucose-induced insulin secretion by pancreatic beta cells.³ Furthermore, like many other growth factors, insulin binding to its cell surface receptor stimulates production of hydrogen peroxide.⁴

In addition, ROS species have been increasingly implicated in the physiological regulation of crucial embryological processes such as the differentiation of cardiomyocytes during fetal development and the emergence of embryonic stem cells.^5,6 So, maybe the old adage is correct: no one or no thing is completely evil.

Now, let’s move in the antithetical direction and observe where ROS can become problematic: insulin resistance pathogenesis. One study found high plasma glucose levels, as can occur in insulin resistance, alters the morphology of mitochondria and causes them to fragment.⁷ Another study established that increased ROS levels are an important trigger for insulin resistance in numerous cellular model settings.⁸ The source of this ROS appears to be in the mitochondria where increased amounts of the ROS hydrogen peroxide are produced.⁹ These mitochondrial metabolic defects have at least partially been reversed by pharmacological or genetic strategies that increase mitochondrial antioxidant levels.¹⁰

Another area ROS can initiate bodily disease lies in cardiovascular disease/CVD. ROS have been shown to be a primary or secondary cause of many cardiovascular events.¹¹ ROS mainly act as a trigger for damage to the vascular endothelium, which leads to endothelial inflammation. Macrophages are then recruited to the area, which leads to ROS generation in the area of the plaque. Next, circulating LDL is oxidized by the ROS leading to foam cell formation and lipid accumulation and eventually the formation of atherosclerotic plaque. Both in vivo and ex vivo studies provide evidence supporting the role of ROS in atherosclerosis formation.^{12 13 14 15}

Cat Stevens’ song has one more fantastic line: “the answer lies within.” For me, “within” here means inside our cells. With regards to ROS, I like to think that our lives will hopefully resemble a neutral teeter totter where both sides are suspended equally in the air. Hopefully, the ROS we generate ourselves and are generated from the outside world will be neutralized by our internal cleansing system. Here is an instance where the status quo needs to be maintained. If we have patients who exist at a neutral teeter totter state, then all we need to do is attempt to help them remain there: tweak their diets a bit, point out where they could be exposed less to whatever environmental toxins are present in their life, identify genetic emunctory weaknesses they have inherited and attempt to strengthen them, etc.

If we have patients where the teeter totter is depressed so that they are not effectively eliminating the ROS, then we must become very good game show contestants. Instead of having to guess which door, 1/2/3, the new car sits behind, we need to become effective sleuths and figure what aspect(s) of their internal cleansing system is not effectively performing their tasks. This requires looking at more than three possible doors and up to 10 or so. We also need to decide which door to open and deal with first. For e.g., a person comes to you with what they say is Lyme’s disease. That seems like an easy fix. Unfortunately, they may just now be expressing the Lyme’s because they moved into a house filled with mold which pushed the teeter totter into an unstable direction that caused a TILT/Toxin Induced Loss of Tolerance. This TILT then allowed the Lyme to express itself. TILT will also be a topic for a future column, as it basically indicates that people have become intolerant to their chemical environment.

Our patients are becoming more complex. This requires us to also become better lateral thinkers and expand our clinical boxes so that we can effectively deal with patients in a manner that actually identifies the cause(s) of their maladies and sets them on a course that will steer their bodies back to a more homeostatic balance.

Like my father, walk the middle of the road with regards to ROS and the antioxidant system. Also, increase your cognitive dexterity so that you can constructively wade through the mine field that science has become and make solid, clinical choices that benefit you, your family, and your patients.

References

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942381/

2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3454471/

3. Leloup C, et al. Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion. Diabetes. 2009;58:673–681.

4. Mahadev KH, et al. The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. Mol Cell Biol. 2004;24:1844–1854.

5. Hernández-García D, et al. Reactive oxygen species: a radical role in development? Free Radic Biol Med. 2010;49:130-143

6. Hom J R, et al. The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation. Dev Cell. 2011;21, 469-478.

7. Yu T, Robotham JL, Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc. Natl. Acad. Sci. USA. 2006;103:2653–2658.

8. Housti, N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006;440:944–948.

9. Anderson EJ, et al. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest. 2009;119:573–581.

10. Hoehn KL, et al. Insulin resistance is a cellular antioxidant defense mechanism. Proc. Natl. Acad. Sci. USA. 2009;106:17787–17792.

11. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiological Reviews. 2007;87:315–424.

12. Bahorun T, et al. Free radicals and antioxidants in cardiovascular health and disease. Internet Journal of Medical Update. 2006;1:1–17

13. Droge W. Free radicals in the physiological control of cell function. Physiological Reviews. 2002;82:47–95.

14. Chatterjee M, et al. Biochemical and molecular evaluation of neutrophil NOS in spontaneously hypertensive rats. Cellular and Molecular Biology. 2007;53:84–93.

15. Ceriello A. Possible role of oxidative stress in the pathogenesis of hypertension. Diabetes Care. 2008;31(Supplement 2):S181–S184. doi: 10.2337