Antioxidants: Taking a Closer Look at Vitamin C and E. Kerry B. Barbera. University of Alabama.

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1 Antioxidants: Taking a Closer Look at Vitamin C and E Kerry B. Barbera University of Alabama kbbarbera@crimson.ua.edu

2 Introduction Oxygen sustains life but it is also responsible for creating oxidative stress in the body. Oxidative stress is caused by free radicals, which are highly reactive and unstable molecules that are formed as normal byproducts of cellular metabolism. 1 Free radicals are highly reactive because they have an odd number of electrons. Acquiring electrons from another molecule can interfere with vital cellular reactions, causing chain reactions that can ultimately lead to cellular damage to proteins, lipids, cell membranes and even DNA. Damage at the cellular level can be pathogenic leading to diseases such as cardiovascular disease and cancer. 2 Exercise, stress and exposure to the environment including smoking, x-rays, and toxins all increase the level of oxidative stress in the body. 2 Antioxidants are substances that interact and neutralize free radicals rendering them safe and prevent oxidative stress in the body. Antioxidants break the free radical destructive pattern by donating an electron to the free radicals or by stopping the chain reaction catalyst. 2 There are two antioxidant defense systems that work synergistically in the body: endogenous antioxidants made by the body, and exogenous antioxidants provided by the diet. Molecules responsible for the exogenous system include the antioxidants glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase. 3 Polyphenols, vitamin C, carotenoids, vitamin A and vitamin E make up the exogenous system. 3 Examples of dietary antioxidants include berries, broccoli, green tea and tomatoes. Antioxidants are also readily available as supplements. The mechanism of action is dependent on the antioxidants because they utilize different mechanisms to help maintain oxidative balance. Two important 1

3 exogenous antioxidants, Vitamin C and Vitamin E, will be discussed in this research review on antioxidants. Science Behind Vitamin C Vitamin C, or ascorbic acid, is a water-soluble vitamin involved in many important reactions in the human body including synthesis of collagen, protein metabolism and certain neurotransmitters. 4 Vitamin C functions as a primary co-factor, a powerful antioxidant, and is essential for normal growth and development in the body. The diet is the primary source for vitamin C because humans lack the enzyme L-gulonolactone necessary to synthesize Vitamin C exogenously. 4 Vitamin C also boosts the body s absorption of nonheme iron while helping to decrease the effects of nutrients such as oxalic acid that negatively impact nonheme iron absorption. 4 The recommended daily allowance (RDA) for Vitamin C is 90 mg/day for men, 75 mg/day for women, and 85 mg/day during pregnancy. 5 Smoking, age, gender, health, nutrient interactions and bioavailability can influence the quantity of Vitamin C required. For example, smokers require an additional 35 mg/day in addition to the RDA because of the increased oxidative damage from smoking. 6 According to the second national report on biochemical indicators of diet and nutrition in the U.S. population, from , vitamin C intakes followed a U-shaped pattern with the lowest intakes observed in year olds. 6 The same report found that females had higher intakes than males and no discrepancies were found between race or ethnic groups. However, 6 percent of the population was found to be vitamin C deficient. 6 2

4 Vitamin C is found naturally in many foods such as berries, citrus fruits, peppers, and broccoli. Found in some fortified cereals, vitamin C is also available as a supplement. Inadequate intake of vitamin C, below 10mg/d, can lead to scurvy. 4 Clinical signs and symptoms can include bleeding gums, fatigue, delayed wound healing, and petechiae. In severe cases of deficiency, abnormal bone matrix and tooth malformation may occur. 6 Vitamin C intakes exceeding the tolerable upper intake level (UL) of 2000 mg/d, usually due to supplement intake, can result in gastrointestinal upset, diarrhea, and kidney stones. 6 Synthetic and natural Vitamin C are chemically identical 7 and according to National Health and Nutrition Examination Survey (NHANES) report, bioavailability is also the same. 6 However, there have been conflicting research data on whether supplementation promotes the same health benefits as natural vitamin C sources. 4 Natural sources of vitamin C found in fruits and vegetables contain other important micronutrients such as fiber and phytochemicals that may promote increased bioavailability and better health benefits than just the intake of vitamin C alone. 7 Vitamin C s chemical structure has two adjacent hydroxyl groups and a carbonyl group. This structure allows it to donate electrons and hydrogen atoms easily to an unstable molecule while remaining stable in its converted form as ascorbate or dehydroascorbic acid. Ascorbic acid s antioxidant functionality can improve shelf life, color and the sensory qualities of the food products. Vitamin C acts as an antioxidant by reducing the available oxygen in food products and their surroundings, preventing oxidation and bacteria growth. Vitamin C can also prevent enzymatic browning and restore vitamin loss during manufacturing. Care must be taken when vitamin C is added 3

5 to a product for its nutritional value as vitamin C is very sensitive to deterioration from exposure to light, temperature, salt and sugar concentrations, oxygen, ph and especially the initial concentration of the ascorbic acid. 8 Processing and packaging are also equally important to maintain appropriate levels of the vitamin. Food or juice products containing vitamin C have a linear decline in regards to storage time and do best when stored at refrigerator temperatures rather than room temperature. 9 This decline is due to the decreasing vitamin C levels as it reduces the available oxygen in the food product. Science behind Vitamin E Vitamin E is a fat-soluble vitamin that is involved in immune function, cell signaling and regulation of gene expression. Vitamin E plays a central role in inhibiting platelet aggregation. 10 It exists in 8 chemical forms: 4 tocopherol and 4 tocotrienol where alpha-tocopherol is the main vitamin actively found in the body. 10 Vitamin E is a fat soluble antioxidant responsible for stopping reactive oxygen species (ROS) formed from lipid oxidation. It is responsible for protecting lipid soluble vitamins and cell membranes from oxidation. Vitamin E donates a hydrogen atom stopping free radical chain reactions, 3,11 which decreases inflammation in the body and may protect it against cardiovascular disease. 11 Vitamin E also protects the oxidation of low-density cholesterol (LDL). Oxidation of LDL s is thought to lead to atherosclerosis. 12 Vitamin C and GSH are responsible for regenerating vitamin E to its active form. This regeneration of vitamin E is thought to be one of the reasons why there is very little prevalence of vitamin E deficiency. 11 4

6 Vitamin E is found naturally in vegetable oils, almonds, avocados, spinach and fish. RDA for adults is 15mg/day with UL of 1000mg/day. 5 Three national survey s reported the average U.S. intake is below the recommended dietary allowance (RDA) levels, 15 IU (11mg) for men and 11.4 IU (8mg) in women, but this low intake could be contributed to poor reporting because the use of cooking fat is often not known or accounted for. 12 Deficiency of vitamin E is quite rare, less than 1 percent of the U.S. population. 6,10 Premature infants born before the transfer of vitamin E from their mother can be born with vitamin E deficiency, also known as erythrocyte hemolysis. 5 Vitamin E absorption is dependent on fat intake. Deficiency of the vitamin is usually associated with a fat malabsorption disorder such as Crohn s disease. Ataxia, peripheral neuropathy, greasy stools, chronic diarrhea, and retinopathy are often symptoms of vitamin E deficiency. 12 Excess vitamin E is stored in the body tissues and if toxicity occurs symptoms may include nausea, gastrointestinal upset, diarrhea and easy bruising or prolonged bleeding. Vitamin E may increase risk of bleeding and caution must be taken with people on blood thinners such as Coumadin or Warfarin. 12 Taking vitamin E supplements for health benefits has not been recommended by any U.S. governmental agency because research has failed to yield consistent results. 11 Synthetically and chemically the two forms may be the similar, however, supplementation in some studies have shown no effect and even unfavorable effects where they have increased disease states. 11 Supplementation does not take into account additional phytochemicals and nutrients consumed in natural sources of vitamin E and the synergistic effects they have on health. 5

7 Highlighting Primary Research-Article 1 Oxidative damage is believed to be responsible for the development of degenerative changes in the brain that may lead to Alzheimer s disease (AD). Previous separate studies have shown that the fat-soluble vitamin alpha tocopherol (Vitamin E) and memantine, a drug used in the treatment of dementia, produced positive effects in the treatment of moderately severe AD. 13 Unfortunately, research is lacking on treatment of both alpha tocopherol and memantine effects in treating mild to moderate AD. 14 One of the longest and largest double-blind, parallel-group, randomized clinical trials to test alpha tocopherol and memantine in their effectiveness of decreasing functional decline in patients with mild to moderate AD was conducted by Dysken, et al. 13 From August 7, 2007 to March 31, 2012, veterans were recruited from 14 VA hospitals taking an acetylcholinesterase inhibitor, a drug that increases the level and duration and of actelychioline, and were diagnosed with possible or probable AD of mild to moderate severity. The veterans were selected based on the study s strict inclusion and exclusion criteria determined to effectively test the study s hypothesis. Six hundred and thirteen participants were randomly assigned either 2000 IU/d of alpha tocopherol, 20 mg/d of memantine, alpha tocopherol plus memantine, or a placebo for the duration of treatment lasting 6 months to 4 years. All participants were assessed every 6 months for any adverse effects of the treatment. After baseline assessments, all participants were assessed annually for alpha tocopherol and memantine serum levels, a physical examination, and a review of medications. Dysken, et al. found that the use of 2000 IU/d of alpha tocopherol was effective in slowing the functional decline of patients with AD by 6

8 19% or 6.2 months, compared with the placebo. These findings support the previous studies in treatment of moderately severe AD. AD is a devastating disease that affects the quality of life of both the patient and the caregiver. The study s results correlated to a 2-hour reduction of caregiver time improving the quality of life of both the caregiver and the patient. Similar findings were not found with the treatment of memantine or the combination of both alpha tocopherol and memanine. Highlighting Primary Research-article 2 Chemotherapy can significantly improve chances of survival in cancer patients, but it produces many toxic side effects. Reactive oxygen/nitrogen species generated by the cancer and chemotherapy treatment are thought to be the etiology behind these toxic side effects that can be debilitating and decrease the quality of life of the cancer patient. 15 Suhail, et al. conducted a prospective random 5-month study to test if supplementation of the antioxidants vitamin C and vitamin E were protective against these harmful side effects and did not interfere with the chemotherapy treatment. 14 Previously, there has been concern that the protective role of antioxidants against ROS may also prove protective of the cancer cells or may interfere with chemotherapy agents that utilize the production of ROS in terminating the cancer cells. 14 Forty women aged between 35 and 65 diagnosed with stage II breast cancer were selected on the study s strict inclusion and exclusion criteria determined to effectively test the study s hypothesis. They were randomly assigned a treatment of chemotherapy alone or the same chemotherapy treatment with a combination of vitamin C and E. Vitamin E tocopheryl acetate 400 mg and vitamin C as Limcee 50mg tablet 7

9 were given daily during the trial and for three weeks post chemotherapy treatment. Blood samples were collected from participants and healthy people for comparison. The study measured the levels of the antioxidants enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione-s-transferase (GST) and glutathione reductase (GR), indicators of antioxidant levels; reduced glutathione (GSH) a non-enzymatic antioxidant; Malondialdehyde (MDA), an indicator of oxidative stress levels. Peripheral lymphocytes were also assessed for DNA damage. These measurements were taken again at the end of the study for comparison. Suhail, et al. found that the control group had significant increases in all levels of antioxidant enzymes, GSH, and a reduction of oxidative stress post treatment compared to the pretreatment levels and the patients treated with chemotherapy alone. The control group also had reduced DNA damage compared to the other groups. Vitamin C and vitamin E restored antioxidant defense normally lowered by chemotherapy and breast cancer. These findings could be very useful in treating breast-cancer patients to offset the often-debilitating toxic side effects of chemotherapy and improving the quality of life for these patients. Summary Oxidative stress is caused by free radicals, which are highly reactive and unstable molecules that are formed as normal by-products in the body. These free radicals can ultimately lead to chronic diseases such as Alzheimer s disease and breast cancer. Antioxidants are substances that neutralize these free radicals rendering them safe and decrease oxidative stress in the body. There are two types of antioxidants: 8

10 exogenous which are produced by the body, and endogenous which come from the diet. Examples of dietary antioxidants include berries, broccoli, green tea and tomatoes. Vitamins C and E are both exogenous antioxidants that scavenge the body for free radicals. Vitamin C is a water-soluble vitamin that is often utilized as an antioxidant in the food industry because it is able to react with the oxygen in the food product decreasing the potential for bacterial growth. Vitamin E is a fat-soluble vitamin and a powerful antioxidant because it protects the cell membranes from oxidative stress and LDL cholesterol from oxidative stress. This decreases the inflammation in the body protecting it against cardiovascular disease. Antioxidants work together in the body to provide many health benefits. Research studies have shown promising results with the treatment of antioxidants against diseases. Vitamin C and E were found to reduce the toxic side effects of breast cancer. Vitamin E was found to decrease the functional decline in Alzheimer s disease, which may prove important in light of a recent report that women over the age of 60 are twice as likely to be diagnosed with Alzheimer s disease than breast cancer. 15 9

11 Resources 1. Addidis, P., Shecterle, L., & St. Cyr, J. (September 2012) Cellular Protection During Oxidative Stress: A Potential Role for D-Ribose and Antioxidants. J Diet Suppl. 9(3): Doi: / Lobo, V., Patil, A., Phatak, A., & Chandra, N. (Jul-Dec 2010) Free Radicals, Antioxidants, and Functional Foods: Impact on Human Health. Pharmacology Rev. 4(8): DOI: / Bouaved, J.,& Torsten, B. (Jul-Aug 2010) Exogenous Antioxidants-Doubled Edged Swords in Cellular Redox State: Health Beneficial Effects at Physiologic Doses Versus Deleterious Effects at High Doses. Oxid Med Cell Longev. 3(4): DOI: /oxim National Institute of Health. Office of Dietary Supplements. Vitamin C Factsheet for Health Professionals. (Reviewed June 5, 2013) Retrieved from Assessed March 11, Whitney, E. & Rolfes, S. Understanding Nutrition. 13 th ed. Belmont, CA: Wadsworth Cengage Learning; Centers for Disease Control and Prevention (2012). Second national Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population. Retrieved from Assessed March 12, Carr, A.C. & Vissers, M. C. (November 2013) Synthetic or Food-Derived Vitamin C- Are They Equally Bioavailable. Nutrients 5 (11): DOI: /nu Marti, N., Mena, P., Cánovas, J., Micol, V., Saura, D. (March 2009). Vitamin C and the role of citrus juices as functional food. Nat Prod Commun. 4 (5): Retrieved online from rus_juices_as_functional_food. Assessed March 12, Cvetković, R. & Jokanović, M.(January 2009) Effect of Preservation and Storage condition on Ascorbic Acid Loss in Beverages. APTEFF. 40:1-7. DOI: /APT C. 10

12 10. Borel, P., Preveraud, D., & Desmarchelier, C. (June 2103) Bioavailability of Vitamin E in Humans: an Update. Nutr Rev. 71(6): DOI: /nure Chow,C.K., & Chow-Johnson, H.S. (January 2013) Antioxidant Function and Health Implications of Vitamin E. J Nut. 7:1-6. DOI: / National Institute of Health. Office of Dietary Supplements. Vitamin E Factsheet for Health Professionals. (reviewed June 5, 2013) Retrieved from Assessed March 11, Dysken, M.W., Sano, M., Asthans, S., Vertress, J.E., Pallaki, M.,Llorente, M.,.& Guarino, P.D. (January 2014) Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease. JAMA. 311(1): DOI: /jama Suhail, N., Bilal, N., Khan, H.Y., Hasan, S., Sharma, S., Khan, F.,...& Banu, N. (February 2012) Effect of Vitamin C and E on antioxidant status of breast-cancer patients undergoing chemotherapy. J Clin Pharm. 37 (1) DOI: /j x. 15. Alzheimer s Association (March 19, 2014). Alzheimer s News. Women in their 60 s twice as likely to develop Alzeimer s Disease over the rest of their lives as they are breast cancer. Retrieved from Assessed March 25,

D. Vitamin K -- Group of naphthoquinones having antihemorrhagic activity.

D. Vitamin K -- Group of naphthoquinones having antihemorrhagic activity. 1. Structures VITAMIN K1; Phytonadione; 2-Methyl-3-phytyl-1,4-naphthoquinone VITAMIN K2; Menaquinone-6 and 7; N=6,7 n 2. Function