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Antioxidants

OxidationChemical rx in which atoms lose electronsMay result in free radical formation

Structure of AtomsAtom: the smallest unit of matter.

Atoms are composed ofNucleus positively charged center portion of the atomElectrons negatively charged particles surrounding the nucleus

OxidationMolecules are composed of atoms.

During metabolic reactions, electrons can be transferredFrom the atoms of one moleculeTo the atoms of another molecule

Oxidation

OxidationOxidation: the loss of electrons from a molecule.

Reduction: the gain of electrons by a molecule.

Oxidation and reduction usually occur together as an exchange reaction.

OxidationStable atoms contain an even number of paired electrons.

Free radical: an atom that has lost an electron and is left with an unpaired electron.

Free radicals are highly reactive and can cause damage to molecules in the cell.

Free Radicals and Diseases

AntioxidantsSubstances that are able to neutralize reactive molecules and reduce oxidative damageResult of metabolic processes and environmental sourcesVitamin C, Vitamin E, beta-carotene, Vitamin A, selenium, iron, zinc, copper and manganese

Vitamin EFunctions: Anti-oxidantGuards against damage to membranes from oxidizing compoundsDeficiency: Rare (premature infants under 3.5 pounds, people unable to absorb fat or metabolize fat properlySuppresses the immune system because vitamin E protects White Blood Cells

Vitamin EToxicity: RareSources:Vegetable oils, nuts and green leafy vegetables, fortified cereals

There's sweet news about hot cocoaHot cocoa tops red wine and tea in antioxidants; may be healthier choiceMore antioxidants per cup than a similar serving of red wine or teaper serving basis, the antioxidant concentration in cocoa was the highest: It was almost 2 times stronger than red wine, 2-3 times stronger than green tea, and 4-5 times stronger than that of black teaNew research underlines antioxidant activity in chocolateVitamin E tocotrienol shows brain protection promise

Vitamin C FunctionsCollagen Formationantioxidantreduce cancer riskhelps absorb iron from foodReduces risk of colds?????probably notLinus Paulings studyNutraIngredients

Vitamin CDeficiency: called scurvypoor formation of collagen in blood vesselsweak vessels result in hemorrhagescan be severe and result in lots of blood loss and deathToxicity: may result inkidney stonesrebound scurvyDestruction of B12Problems with acid/base balance

Vitamin C: RDA 90/75 mg/dayFoods rich in vitamin C:1 cup fresh squeezed orange juice: 124 mg1 cup canned o.j.: 84 mgSmokers RDA = +35 mg/daySome of vitamin C is sacrificed in reducing the oxidants of cigarette smokeVitamin C intake offers protection against stomach cancer

Beta-Carotene-provitaminFunctionsWeak antioxidantEnhance immune systemProtect skin and eyesDeficiency/toxicity

Beta-Carotene-provitaminNo RDASources

Vitamin A FunctionsVision: helps with conversion of light energy to electrical energy in eyeCell differentiation-maintenance of linings:helps produce the CHO normally found in mucous Bone growth:helps with remodeling growing bones

Vitamin A DeficiencyOne year supply in fat and liver of most people: So deficiencies are rareBone growth and remodeling problemsshape changesLinings deteriorateGI tract: diarrheaRespiratory tract: infectionsurogenital tract: infections, kidney stonesImpaired night vision and day vision

Vitamin A ToxicitiesBones:decalcification, joint painNervous systemloss of appetite, irritability, muscle weaknessLiver enlargementjaundiceBlood: RBCs loose hemoglobinBleeding induced easily

Beta carotene and Vitamin A

Vitamin A RDA= 700 RE for females; 900 RE for males.RE= Retinol EquivalentRetinol is the active form of vitamin AOther molecules can be metabolized to make Retinol, thus retinol equivalentse.g.: beta carotene can be modified to make retinolbeta carotene is found in carrots and other deep orange and green vegetables1 RE= 1 microgram of retinol1 RE= 3.3 IU retinol1 RE = 12 micrograms of beta carotene

SeleniumFunctionsAntioxidant systemThyroxine and immune functionDeficiencyKeshan diseaseImpaired immune response, cognitive function, muscle pain, wastingThe Link between Selenium and Chemoprevention: A Case for Selenoproteins -- Diwadkar-Navsariwala and Diamond 134 (11): 2899 -- Journal of Nutrition

Selenium RDA 55 mg/daySourcesNutsSeafoodPasta

Disorders related to OxidationCancer - DefinitionsCancer: uncontrolled growth and spread of abnormal cellsTumor: mass of cancer cellsbenign tumor (non-harmful, non-invasive)malignant tumor (harmful, invasive)Metastatic Cancer: spreading

Cancer FactsUS men have a 1 in 2 lifetime riskUS women have a 1 in 3 lifetime risk1,220,000 new malignant cancer cases in 2000552,000 cancer deaths in 2000Cancer the Top Killer for Those Under 85 Jan 20, 2005

Cancer TrendsJNCI, 19991990-1996All cancer incidence declined by 2.2% -4.1% males -0.5% femalesUSATODAY.com - Cancer deaths lowest in 7 decades

US Mortality, 2000Source: US Mortality Public Use Data Tape 2000, National Center for Health Statistics, Centers for Disease Control and Prevention, 2002.

1.Heart Diseases710,76029.6 2.Cancer553,09123.0

3.Cerebrovascular diseases167,661 7.0 4.Chronic lower respiratory diseases122,009 5.1 5.Accidents (Unintentional injuries)97,900 4.1 6.Diabetes mellitus69,301 2.9 7.Influenza and Pneumonia65,313 2.7 8.Alzheimers disease49,558 2.1 Nephritis37,251 1.5

10.Septicemia31,224 1.3 RankCause of DeathNo. of deaths% of all deaths

2004 Estimated US Cancer Deaths*ONS=Other nervous system.*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2003.Men 285,900Women 270,60025%Lung & bronchus15%Breast10%Colon & rectum6%Pancreas6%Ovary4%Leukemia3%Non-Hodgkin lymphoma3%Uterine corpus2%Brain/ONS2%Multiple myelomaLung & bronchus32%Prostate10%Colon & rectum10%Pancreas5%Leukemia5%Non-Hodgkin4% lymphomaEsophagus4%Liver/intrahepatic3% bile ductUrinary bladder3%Kidney3%

The Cancer Development ProcessInitiationAlterations in DNAminutes - daysCauses:radiationchemical carcinogensviruses

The Cancer Development ProcessPromotionlocking DNA alterationsfailure of DNA repair mechanismsmonths - years

The Cancer Development ProcessCancer ProgressionUncontrolled growth of cancer cellsmalignancy and metastasisweeks to years

Cancer Developmenthttp://science.education.nih.gov/supplements/nih1/cancer/activities/activity2_animations.htm

Diet and Cancer DevelopmentInitiationDietary sources of carcinogensaflatoxin mold from peanutsbenzopyrene from charbroiled meatsnitrosamine from cured meatsAICR Press Corner - Recent NewsProtectionphytochemicalsantioxidantsdietary fiberStudy will assess effect of tomato oil on precancerous prostate changes

Diet and Cancer DevelopmentPromotionFat and PUFAexcess alcoholProgressionexcess Fat and caloriesAlaska Journal of Commerce Online

Diet and CancerACS 2000One third of cancer deaths in US is due to cigarette smokingOne third of cancer deaths in US is due to diet5-10% of cancers are hereditaryNutraIngredients

1999 ACS Dietary GuidelinesChoose most of the foods you eat from plant sources.Five A DayHealthy fruit and veg compounds being lost in processinglow in fat and calorieshigh in folic acid, vitamin C, beta-carotenehigh in fiberhigh in phytochemicals ABC News: Turn to Tomatoes for Prostate HealthFOXNews.com - Health - Vitamin D May Lower Some Cancer Risk

Trends in Consumption of Recommended Vegetable and Fruit Servings (5 or more) for Cancer Prevention, Adults 18 and Older, US, 1994-2000* Includes fewer than 50 states and the District of Columbia. All other prevalences include the 50 states and District of Columbia.Source: Behavioral Risk Factor Surveillance System, 1994, 1996, 1998, 2000, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 1997, 1999, 2000, 2001.Prevalence (%)1994*199619982000

Cardiovascular Disease (CVD)Risk factorsSmokingHypertensionHigh LDLObesitySedentary life styleNutrition Notes: How to fight inflammation - Nutrition Notes - MSNBC.com

CVD and AntioxidantsScavengersDonates electronsReduction of inflammationEnhances immune systemReduction of blood coagulation

Vision impairmentMacular degenerationPromising resultsCataractsMixed results

**Molecules are composed of atoms. We are constantly breaking down molecules of food and air into their component atoms, and then rearranging these freed atoms to build the different types of molecules our body needs.Atoms have a central core that is + charged (nucleus)Electrons (- charge) revolve around nucleus+ and attractions keep atom stable.Atoms may lose electrons during metabolism loss of electrons is called oxidation (it is fueled by oxygen) We also gain electrons during metabolism in an even exchange. Exchange reaction.Stable atoms have an even number of electrons orbiting in pairs. When a stable atom loses an electron during oxidation, it is left with an odd number of electrons in outer most shell. It is now an unpaired electron. In rare cases atoms with unpaired electrons in their outermost shell remain unpaired. Free radicals.

Free radicals can destabilize other molecules and damage our cells*One of the most significant sites of free radical damage is the cell membrane. May affect all systems affected by this cell.Other sites of damage include LDL, cell proteins and our genetic material (DNA). May increase our risk for heart disease and cancer and cause our cells to die prematurely.*Certain antioxidant vitamins donate their electrons or hydrogen molecules to free radicals to stabilize them.Antioxidant minerals function within complex antioxidant enzyme systems that convert free radicals to less damageing substances that are excreted by our bodies. These enzymes also break down fatty acids that have become oxidized. In breaking down the fatty acids they destroy the free radicals associated with the oxidized fatty acids.SOD converts free radicals to hydrogen peroxidecatalase removes hydrogen peroxide from our bodies by converting it to water and hydrogenglutathione peroxidase also removes hydrogen peroxide and stops the production of free radicals in lipidsAntioxidants, vit E, C possibly A, beta-carotene and seleniumCopper zinc and manganese are part of SOD.Iron cofactor for catalase antioxidant enzymeEnvironmental - air pollution, cigarette smoke

Either act as antioxidant or are part of enxyme that does (Zn, Cu, Mn)*Copper zinc and manganese part of SOD - cofactors*Once it donates an electron (it is oxidized), it is either excreted or recycled back into active vita E through the help of other antioxidants like vit COther roles: critical for normal fetal and early childhood development of nerves and muscles as well as maintenance of their function. Enhances immune function by protecting WBC. Improves absorption of vit A if intake is low.As oil in diet increases, need for vit E increases

Generally no deficiency. If no fat consumed may be a problem. Only takes a little.

May be seen in premature infants

Non-toxic below 1000 mgResearch done on 400-800mg/day

RDA 15 mg/day, 10x RDA considered a megadose or 150 mg but UL = 1000 mg or about 67x RDA*Safe dose probably 2000 mg, but some people experience fatigue, weakness at 1000 mg

Can destroy vit K in gut but not a problem.

1alpha tocopherol = 1 mg of active vit EIn supplements, 1 UI = .67 mg (natural) or .45 mg (artifical)*2003 per serving basis, the antioxidant concentration in cocoa was the highest: It was almost 2 times stronger than red wine, 2-3 times stronger than green tea, and 4-5 times stronger than that of black teaAntioxidant-rich cocoa is also found in many different products including desserts, sauces, liqueurs and candy bars, which differ widely in their cocoa content. But when given a choice between getting your antioxidant fix from a cup of cocoa or a candy bar, it is better to go with the drinkable stuff, says Lee. A normal 40-gram bar of chocolate contains about 8 grams of saturated fat, compared to only 0.3 grams in an average cup of hot cocoa, he notes.

*Best known role involved in synthesizing the protein collagen. Important for wound healing. Prevention of scurvey.Antioxidant donates electrons to free radicals. Acts in the extracellular fluid, water soluble vitamin. Acts in lungs(poluntants) and stomach (nitrosamines)Enhances immune system , assists in synthesis of DNA, various hormones. Appropriate levels of thyroxine. Enhanced absorption of ironCollagen found in connective tissue, bones, teeth, tendons, blood vesselsImportant in wound healing.

May protect against infectionImmune function. Vit C in WBC protection against oxidative damage

Vit C changes 2 AA (lysine and proline) to Hydrolysine and hydroproline. Only found in collagen. Rope like structureMay reduce duration and severity but not incidence of colds.*Symptoms weakness, opening of previously healed wounds, slower wound healing, bone pain, bleeding gums, pinpoint hemorhages.

Rebound scurvy newborn dependent on high maternal levels

Megadose is defined as 10x RDANot toxic, but there can be side effects. Nausea, diarrhea, nosebleeds and abdominal cramps.Kidney stones in people who have preexisting kidney disease.*Provitamins are inactive forms of vitamins that the body cannot use until they are converted to their active form. We convert beta-carotene to vitamin A or retinol.Works as antioxidant in fat, like vit E. Other carotenoids may be stronger, lycopene and lutein. Research going on Enhances our ability to fight illness and diseaseProtects skin from UV light and eyes from age-related vision impairmentNo known deficiency although may be the main source of vit ANo toxicity except yellow skin color

*6-10 mg beta-carotene/day may reduce incidence of some diseases (cancer, CHD)Cancer study-increased rates of death, prostate and stomach cancer (done on smokers)*Role as antioxidant under investigation at this time. May scavenge free radicals like C and E.Differentiation, the process by which cells mature into highly specialized cells critical to development of healthy organs and effectively functioning body systems.Epithelial tissues and their mucus producing cells. Lungs, eyes, intestines, stomach. Protective barrierAlso differentiation of immune cells (T-cells) which fight infection.Helps in remodeling bones, breaking down old bone so that new longer and stronger bone can develop. Reproduction. Exact role unclear but appears necessary for sperm production in men and for fertilization to occur in womenRetin a applied to skin for acne, accutane taken orally. Contain dirivatives of vit a but vit a will not work alone on acne.

*Toxic at 4x RDA Birth defects and spontaneus abortion*Works with antioxidant system as part of glutathione peroxidase enzyme system. Helps spare vit E and prevents oxidative damage to our cell membranes.Needed for the production of thyroxine, hormone produce in the thyroid responsible for basal metabolism and body temperatureAppears to play a role in the immune system.Deficiency seen in selenium poor region in China Keshan disease. A heart disease seen in children.No toxicity from foods. If supplement use is high may experience nausea vomiting, brittle hair and nails, cirrhosis of the liver.*Disorders related to oxidation*Ranks second only to heart disease as a leading cause of death and disability in the US*New data for 1999 show that death rates for all cancers combined continued to decline in the United States. However, the number of cancer cases can be expected to increase because of the growth and aging of the population in coming decades, according to a report released today.The single most important risk factor for cancer is age. Because the U.S. population is both growing and aging, the authors focused on how, even if rates of cancer remain constant, the number of people diagnosed with cancer will increase

*Cancer is 2nd leading cause of death.Cancer society identifies five primary factors.Tobacco use lung larynx, mouth and esophagus. (also heart disease, stroke,emphysema90% of all lung cancer due to tobacco use*Exposure to a carcinogenEntry of the carcinogen into a cellInitiation of cancer as the carcinogen alters the cells genetic material in some way (cacinogenesis)*4. Acceleration by other carcinogens, called promoters, so that the cell begins to multiply out of control

Damage is locked into the genetic material in cells.Compounds that increase cell division are called promoters. These are thought to promote cancer either by decreasing the time available for repair enzymes to act or by encouraging cells with altered DNA to develop and grow. Some promoters are estrogen, alcohol and possibly a high intake of dietary fat. Bacterial infections in the stomach are also suspected agents. Helicobacter pylori my ultimately promote stomach cancer.*. Spreading of cancer sells via blood and lymph (metastasis): disruption of normal body functionsEarly in this stage the immune system may find the altered cells and destroy them, or the cancer cells may be so defective that their own DNA limits their ability to grow and they die. If nothing impedes cancer cell growth one or more tumors eventually develop that are large enough to affect body functions.*Figure 3 - The stages of tumor development. A malignant tumor develops across time, as shown in this diagram. This tumor develops as a result of four mutations, but the number of mutations involved in other types of tumors can vary. We do not know the exact number of mutations required for a normal cell to become a fully malignant cell, but the number is probably less than ten. a. The tumor begins to develop when a cell experiences a mutation that makes the cell more likely to divide than it normally would. b. The altered cell and its descendants grow and divide too often, a condition called hyperplasia. At some point, one of these cells experiences another mutation that further increases its tendency to divide. c. This cells descendants divide excessively and look abnormal, a condition called dysplasia. As time passes, one of the cells experiences yet another mutation. d. This cell and its descendants are very abnormal in both growth and appearance. If the tumor that has formed from these cells is still contained within its tissue of origin, it is called in situ cancer. In situ cancer may remain contained indefinitely. e. If some cells experience additional mutations that allow the tumor to invade neighboring tissues and shed cells into the blood or lymph, the tumor is said to be malignant. The escaped cells may establish new tumors (metastases) at other locations in the body.

*Methods that prevent initiation is a family of enzymes in cells that can detoxify and speed up excretion of cancer-producing chemicals. (Phase 2 enzymes). Some dietary phytochemicals increase the amount of these enzymes in the body. Enzymes can travel up and down the DNA double helix, repairing broken components and correcting defects. About 99% of the time, the repair enzymes find the damage and correct it before the cell divides again and thus undergoes mutation.

Oxidative damage to DNA likely cause. Evidence that selenium (above RDA) has an anticancer effect in humans. More evidence needed before recommendations madeAlso enhance immune system which assists in the destruction and removal of precancerous cells and inhibit the growth of cancer cells and tumors

Fiber still uncertain to its role. Well designed studies found no protection against colon cancer. However, the majority of of evidence suggests a protective role.

*Excess body fat linked to increased synthesis of estrogen(promoter)Strongest evidence is for saturated fat and polyunsaturated fat. Saturated fat is linked to increased risk of prostate cancer. PUFA tend to oxidize when exposed to high temp. When they enter the body they may set up a condition of oxidative stress. Colon and rectum.Some evidence that omega 6 promote and omega 3 protect.Alcohol contributes to cancers of the throat, liver, bladder, breast, and colon (especially if diet is low in folate). Increased cell turnover and liver metabolism of carcinogens are the main mechanism.Diets high in calories do seem to promote cancer, especially in the lab. Still trying to untangle the effects of fat alone from those of energy content of the diet*Inherited mutations cannot account for the dramatic differences in cancer rates around the world. In poorer countries, cancers of the stomach, liver, mouth, esophagus and uterus are most common.In affluent countries, cancers of the lung, colon-rectum, breast and prostate predominate. Twin studies 44,788 twins researchers found tht inherited genetic factors make up only a minor contribution to the susceptibility to most types of cancer. For nearly all body sites, the researchers found that risk factors in the environment shared by a family can inc*

Phytochemicalscarotonoids act as antioxidantsFlavonoids( berries,citrus fruit, soy products, etc) act as antiioxidants

Organosulfur (garlic, onions, etc) may speed production of carciongen-destroying enzymesIndoles (broccoli and other cruciferous veg) may trigger production of enzymes that block DNA damage from carcinogens

See page 59 of text for complete list*Other factors:Low HDL

C-Reactive protein marker that indicates degree of a low grade inflammation.It may be responsible for the plaque (which is inside our arteries) to become fragile and burst and break away from the sides of the arteries. It may then form a clot that closes off the vessels of the heart or brain, leading to a heart attack or a stroke.High c-reactive protein and high LDL 9x the risk of heart attack.*Inflammation is defined as a response to injury from infectious, physical, or chemical agents. It is now widely accepted that inflammation plays a major role in the development and progression of atherosclerosis. The initial injury that occurs in atherosclerosis is damage to the endothelial cells lining the blood vessels. Some of the factors leading to the injury include increased levels of oxidized low density lipoproteins (LDL-C) found in dyslipidemia, free radicals formed by cigarette smoking, possible infectious agents, and the shearing stress placed on endothelial cells due to hypertension.[6] The endothelial cell wall injury triggers a cascade of events and the secretion of mediators that modulates the inflammatory response. The homeostatic properties of the surface of the endothelial cell become procoagulant allowing leukocytes and platelets to adhere. Nuclear factor kappa- B is released[7] and initiates the transcription of cytokines involved in inflammation including tumor necrosis factor- (TNF-), chemokines such as monocyte chemoattractant protein-1 (MCP-1) and the vascular cell adhesion molecule-1 (VCAM-1). Monocyte chemoattractant protein-1 attracts circulating monocytes to the site of injury, and through binding to VCAM-1, monocytes adhere to the endothelial cell wall. The monocytes are then able to migrate across the endothelial barrier into the intima layer and differentiate into macrophages. They phagocytosize the increased amount of lipoproteins from the LDLs and transform into foam cells. These cells secrete pro-inflammatory molecules such as interleukin-1 (IL-1), interleukin-6 (IL-6), and TNF-; all of which can contribute to additional leukocyte accumulation and induce smooth muscle proliferation and migration from the medial layer into the intima. The arterial wall begins to thicken as more LDLs are taken up by macrophages and an atheroma is formed. An atheroma is a core of lipids and necrotic cellular debris resulting from dying foam cells. The smooth muscle cells produce collagen which forms a fibrous cap over the atheroma. In order to compensate for the growth of the atheroma, the vessel dilates and allows for continuous blood flow. Eventually, the size of the atherosclerotic plague encroaches on the lumen of the blood vessel causing a reduction in blood flow. Plague develops most commonly in areas of increased turbulence where direction of blood flow changes at branches and bifurcations. The continuous elaboration of the proteolytic enzyme, matrix-metalloproteinases (MMP), by the macrophages under the fibrous cap initiates a breakdown of the collagen. As a result, the cap weakens and eventually ruptures (Figure 1). The atheroma and its thrombotic material is exposed and leads to the formation of a thrombus and ensuing emboli. This is the precipitating event that can lead to a myocardial infarction. *Oxidized LDL particles stimulates the buildup of plaque formation.

Prevent the rupture of plaque in the blood vessels.

Anticoagulant properties.*High levels of antioxidants and zinc reduce risk of age-related macular degeneration dec risk by 25% No effect on cataract formation in this cocktail

Heart disease - oxidative damage of LDL promotes blockages in arteries. Vit E may prevent or delay CHD by limiting oxidation of LDL. May prevent formation of blood clots. Observational studies: 30-40% lower. Clinical trials at 400 IU - no impactCancer - Protect against free radicals which contribute to cancer. Enhances immune function. Inconclusive. Perhaps dec incidnce of breat cancer but not colon cancercataracts - conflicting results. Observational inc lens clarity, in smokers, no effect

Ninety percent of AMD patients have so-called "dry" AMD. While there is currently no cure for dry AMD, a study published by the National Eye Institute last year showed that taking a combination of zinc, vitamins C and E and beta-carotene, may slow disease progression.