9.1 Antioxidants

Antioxidants

The antioxidant vitamins and minerals include the following:

• Vitamin E
• Vitamin C
• Selenium
• Iron
• Copper
• Zinc
• Manganese
• Riboflavin

In this section, we are going to cover vitamin E, vitamin C, and selenium in detail because being an antioxidant is their primary function.

Subsections:

• 9.11 Free Radicals & Oxidative Stress
• 9.12 What is an Antioxidant?
• 9.13 Meaningful Antioxidant(s)
• 9.14 Too Much of a Good Thing? Antioxidants as Pro-oxidants

Free Radicals & Oxidative Stress

Before you can understand what an antioxidant is, it is important to have an understanding of oxidants. As you have learned already, oxidation is the loss of an electron as shown in Figure 9.111.

Figure 9.111 The purple compound is oxidized; the orange compound is reduced1

Some important terms to understand:

Free Radical – a molecule with an unpaired electron in its outer orbital.

The following example shows normal oxygen losing an electron from its outer orbital and thus, becoming an oxygen free radical.

Figure 9.112 Normal oxygen is converted to an oxygen free radical by losing one electron in its outer orbital, leaving one unpaired electron.

Free radicals are highly reactive because they actively seek an electron to stabilize (pair with) the unpaired electron within the molecule.

Reactive Oxygen Species (ROS) – an oxygen-containing, free radical species. Some of the most common ROS are (● symbolizes radical):

• 2
  Superoxide (O ●)
• Hydroxyl Radical (●OH)
• 2
  Hydrogen Peroxide Radical (HO ●)
• 2
  Peroxyl Radical (ROO ●)
• Alkoxyl Radical (RO●)
• Ozone (O₃)
• Singlet Oxygen (1O₂)
• Hydrogen Peroxide (H₂O₂)

Oxidative Stress – the imbalance between the production of ROS/free radicals and the body’s

ability to quench them.

Free radicals can be generated by a variety of sources that can be classified as endogenous (within the body) and exogenous sources (outside the body). The link below is a figure that shows how ROS can be generated from each of these sources.

The Required Web Link below does a good job explaining what oxidative stress is, how free radicals can be formed, how they are neutralized by antioxidants, where we get antioxidants.

Required Web LinkWhat is Oxidative Stress, Free Radicals & Antioxidants

Figure 9.113 shows that inflammation caused by hitting your thumb with a hammer, exposure to UV light, radiation, smoking, and air pollution are all sources of free radicals.

Figure 9.113 Some sources of free radicals

So, we have these free radicals searching for an electron, what’s the big deal? The problem arises if the free radicals oxidize LDLs, proteins, or DNA as shown below.

Figure 9.114 Free radicals can attack LDLs, proteins, and DNA2,3

Oxidized LDL is more likely to contribute to atherosclerosis (hardening of the arteries) than normal LDL. Protein oxidation is believed to be involved in the development of cataracts. Cataracts are the clouding of the lens of the eye. If nucleotides within DNA are oxidized, it can result in a mutation. A mutation is a change in the nucleotide or base pair sequence of DNA. Mutations are a common occurrence in cancer.

References & Links

1. http://en.wikipedia.org/wiki/Image:Gulf_Offshore_Platform.jpg

Links

What is Oxidative Stress, Free Radicals & Antioxidants – https://www.youtube.com/watch?v=9OgCjhAFCC0

Cataract Vision Simulator – https://www.aao.org/eye-health/diseases/cataracts-vision- simulator

What is an Antioxidant?

We are now ready to move on to antioxidants, which as their name indicates, combat free radicals, ROS, and oxidative stress. As a humorous introduction, the link below is to a cartoon that shows Auntie Oxidant kicking free radicals out of the bloodstream.

Required Web LinkAuntie Oxidant

Unfortunately, it’s not quite that simple. You have probably heard the saying “take one for the team.” Instead of taking one for the team, antioxidants “give one for the team.” The ‘giving’ in this example is the donation of an electron from itself to a free radical, in order to regenerate a stable compound, as shown in Figure 9.121.

Figure 9.121 Regeneration of normal oxygen from oxygen free radical by the donation of an electron from an antioxidant

Donating an electron is how vitamins (A, C & E) act as antioxidants. Minerals, on the other hand, are not antioxidants themselves. Instead, they are cofactors for antioxidant enzymes.

These antioxidant enzymes include:

• Superoxide dismutase (SOD): uses copper, zinc, and manganese as cofactors (there is more than one SOD enzyme); converts superoxide to hydrogen peroxide and oxygen1.

• Catalase: uses iron as a cofactor; converts hydrogen peroxide to water1.

• Glutathione peroxidase (GPX): is a selenoenzyme that converts hydrogen peroxide to water. It can also convert other reactive oxygen species (ROSs) to water1.

• alpha-Lipoic acid: reacts with reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects membranes by interacting with vitamin C, which may in turn recycle vitamin E3.

• Peroxiredoxin: participates directly in eliminating hydrogen peroxide (H₂O₂) and neutralizing other reactive oxygen species (ROS)4.

The actions of some of these enzymes is shown in Figure 9.122.

Figure 9.122 Antioxidant enzymes that use minerals as cofactors

Antioxidants are thought to work in concert with one another, forming what is known as the

antioxidant network. For example, vitamin E, vitamin C, and selenium often work together to process a single ROS as shown in Figure 9.123. (You do not have to memorize the intermediates right now, but as you get through the various subsections, they should start to make sense) Notice how the Vitamin E Cycle processes the ROS (reaction on the bottom left,) and then works with the Vitamin C Cycle, and finally the Selenium Cycle to eliminate the intermediate chemicals.

Figure 9.123 An example of an antioxidant network2

References & Links

• Gropper SS, Smith JL, Groff JL. (2008) Advanced Nutrition and Human Metabolism. Belmont, CA: Wadsworth Publishing.
• Packer L, Weber SU, Rimbach G. (2001) Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling. J Nutr 131(2): 369S-373S.
• Packer L, Witt EH, Tritschler HJ. (1995) alpha-Lipoic acid as a biological antioxidant. Free Radic Biol Med. 19(2):227-50.
• Yuan J, Murrell GA, Trickett A, Landtmeters M, Knoops B, Wang MX. (2004) Overexpression of antioxidant enzyme peroxiredoxin 5 protects human tendon cells against apoptosis and loss of cellular function during oxidative stress. Biochim Biophys Acta. 1693(1):37-45.

Link

Auntie Oxidant – http://www.ibiblio.org/Dave/Dr-Fun/df200005/df20000523.jpg

Meaningful Antioxidant(s)

There is a lot of confusion among the public on antioxidants. For the most part, this is for a good reason. Many food companies put antioxidant numbers on the packages that sound good to consumers, who often have no idea how to interpret them. Thus, it is increasingly important to have an understanding of what a meaningful antioxidant actually is.

A meaningful antioxidant has two characteristics (these are based on the assumption that the compound is an antioxidant):

• Found in appreciable amounts in a location where there are free radicals/ROS that need to be quenched
• It is not redundant with another antioxidant that is already providing that function

What do these mean? Let’s consider the example of lycopene and vitamin E (alpha-tocopherol), which are both fat-soluble antioxidants. In a lab setting (in vitro), lycopene has been shown to be 10x more effective in quenching singlet oxygen than alpha-tocopherol1. However, when you look at the concentrations found in the body, there is far more alpha-tocopherol than lycopene as shown below:

• LDL – 13x more alpha-tocopherol than lycopene1.
• Prostate – 162x higher alpha-tocopherol than lycopene concentrations
• Skin – 17 to 269x higher alpha-tocopherol than lycopene concentrations
• Plasma – 53x higher alpha-tocopherol than lycopene concentrations1

Thus, despite the fact that lycopene is a better antioxidant in vitro, alpha-tocopherol is likely the more meaningful antioxidant in the body as evidenced by the fact that its concentration so much higher in the various tissues (locations of need.) In addition, if lycopene and alpha- tocopherol had similar antioxidant functions, lycopene’s potential antioxidant action is redundant to alpha-tocopherol’s antioxidant function and thus, is less likely to be a meaningful antioxidant.

References & Links

1. Erdman, J.W., Ford, N.A., Lindshield, B.L. Are the health attributes of lycopene related to its antioxidant function? Arch Biochem Biophys, 483: 229-235, 2009.

Too Much of a Good Thing? Antioxidants as Pro-oxidants

A clinical trial once found that high-dose beta-carotene supplementation increased lung cancer risk in smokers2. This is an example of findings that support that high doses of antioxidants may be “too much of a good thing”, causing more harm than benefit. The parabolic, or U-shaped figure, below displays how the level of nutrient concentration or intake (horizontal axis) relates to an antioxidant measure (vertical axis). The lowest level of antioxidant intake or tissue concentration results in nutrient deficiency if the antioxidant is essential (vitamins and minerals). Intake levels above deficient, but less than optimal, are referred to as low suboptimal. Suboptimal means the levels are not optimal. Thus, low suboptimal and high suboptimal sandwich optimal. The high suboptimal level is between optimal and where the nutrient becomes toxic.

Figure 9.142 How the levels of nutrient concentration or intake alters antioxidant measures in the body. Adapted from reference 1

Another example of this phenomenon can be seen when we look at DNA damage in the prostate gland of dogs as it relates to toenail selenium concentration measurements, which are a good indicator of long-term selenium status1. Researchers found that when they plotted prostate DNA damage (antioxidant measure) against toenail selenium status (nutrient concentration or intake) that it resulted in a U-shaped curve like the one shown above1. Thus, it is good to have antioxidants in your diet, but too much can be counterproductive.

References & Links

• Waters DJ, Shen S, Glickman LT, Cooley DM, Bostwick DG, et al. (2005) Prostate cancer risk and DNA damage: Translational significance of selenium supplementation in a canine model. Carcinogenesis 26(7): 1256-1262.

• Peto R, Doll R, Buckley JD, Sporn MB. Can dietary beta-carotene materially reduce human cancer rates? Nature 290, 201-208, 1981.