The Fat-Soluble Vitamins: A, D, E, and K Chapter 11

Introduction How fat-soluble vitamins differ from water-soluble vitamins Require bile for digestion and absorption Travel through lymphatic system Many require transport proteins in bloodstream Excesses are stored in liver and adipose Risk of toxicity is greater RDA over time is what matters

Vitamin A and Beta-Carotene Vitamin A, 1st fat-soluble vitamin studied Precursor – beta-carotene, also a pigment Absorption and conversion Beta-carotene Three main active forms (retinoids) retinol, retinal, and retinoic acid Conversion to other active forms

Conversion of β-carotene to Vitamin A Retinol, the alcohol form Retinal, the aldehyde form Retinoic acid, the acid form Cleavage at this point can yield two molecules of vitamin A* *Sometimes cleavage occurs at other points as well, so that one molecule of beta-carotene may yield only one molecule of vitamin A. Furthermore, not all beta-carotene is converted to vitamin A, and absorption of beta-carotene is not as efficient as that of vitamin A. For these reasons, 12 μg of beta-carotene are equivalent to 1 μg of vitamin A. Conversion of other carotenoids to vitamin A is even less efficient. Figure 11.1: Forms of Vitamin A. In this diagram, corners represent carbon atoms, as in all previous diagrams in this book. A further simplification here is that methyl groups (CH3) are understood to be at the ends of the lines extending from corners. (See Appendix C for complete structures.) Beta-carotene, a precursor

Vitamin A and β-Carotene Digestion and absorption of vitamin A SI to lymphatic system Lymphatic system to liver Storage in liver Retinol-binding protein (RBP) for transport in serum Cells that use vitamin A have receptors that dictate its job in that cell

Vitamin A and β-Carotene Roles in the Body Regulation of gene expression Major roles Vision Protein synthesis and cell differentiation Reproduction and growth

Vitamin A and β-Carotene Roles in the Body Retinol Supports reproduction Major transport and storage form Retinal Active in vision Retinoic acid Regulates cell differentiation, growth, and embryonic development

Conversion of Vitamin A Compounds Retinyl esters (in animal foods) Beta–carotene (in plant foods) IN FOODS: Retinol (supports reproduction) Retinal (participates in vision) Retinoic acid (regulates growth) IN THE BODY: Figure 11.2: Conversion of Vitamin A Compounds. Notice that the conversion from retinol to retinal is reversible, whereas the pathway from retinal to retinoic acid is not.

Vitamin A and β-Carotene Roles in the Body Vision Cornea maintenance Retina Photosensitive cells Rhodopsin (remember opsin?) Repeated small losses of retinal Need for replenishment due to oxidation from visual activity

Vitamin A’s Role in Vision

As light enters the eye, rhodopsin within the cells of the retina absorbs the light. Retina cells (rods and cones) Light energy Figure 11.3: Vitamin A’s Role in Vision. The retina receives the image formed by the lens and converts light energy into chemical energy and nerve signals that reach the brain via the optic nerve. Cornea Eye Nerve impulses to the brain

The cells of the retina contain rhodopsin, a molecule composed of opsin (a protein) and cis-retinal (vitamin A). cis-Retinal trans-Retinal Figure 11.3: Vitamin A’s Role in Vision. The retina receives the image formed by the lens and converts light energy into chemical energy and nerve signals that reach the brain via the optic nerve. As rhodopsin absorbs light, retinal changes from cis to trans, which triggers a nerve impulse that carries visual information to the brain.

Vitamin A and β-Carotene Roles in the Body Protein synthesis & cell differentiation Epithelial cells on all body surfaces Skin Mucous membranes (Linings) Ex: GI lumen lining Ex: Respiratory tract linings Goblet cells (secrete mucous)

Mucous Membrane Integrity

Vitamin A maintains healthy cells in the mucous membranes. Without vitamin A, the normal structure and function of the cells in the mucous membranes are impaired. Goblet cells Figure 11.4: Mucous Membrane Integrity. Mucus

Vitamin A (retinol) and β-Carotene Roles in the Body Reproduction and growth Sperm development Normal fetal development Growth of children Weight and Height Bone remodeling Antioxidant, cancer protection Beta-carotene, not Vitamin A

Vitamin A Deficiency Vitamin A status depends on Def. symptoms can take 1-2 yrs to appear for adult, much sooner for growing child Vitamin A status depends on Adequacy of stores, 90% in liver Protein status for RBP mfg. Consequences of deficiency Risk of infectious diseases Blindness Death

Vitamin A Deficiency Infectious diseases Night blindness Measles, pneumonia, diarrhea Malaria, lung diseases/infections, HIV- AIDS Night blindness Inadequate supply of retinal to retina Blindness (xerophthalmia) Lack of vitamin A at the cornea Develops in stages

Figure 11.5: Vitamin A–Deficiency Symptom—Night Blindness. These photographs illustrate the eyes’ slow recovery in response to a flash of bright light at night. In animal research studies, the response rate is measured with electrodes.

Figure 11.5: Vitamin A–Deficiency Symptom—Night Blindness. These photographs illustrate the eyes’ slow recovery in response to a flash of bright light at night. In animal research studies, the response rate is measured with electrodes.

Figure 11.5: Vitamin A–Deficiency Symptom—Night Blindness. These photographs illustrate the eyes’ slow recovery in response to a flash of bright light at night. In animal research studies, the response rate is measured with electrodes.

Figure 11.5: Vitamin A–Deficiency Symptom—Night Blindness. These photographs illustrate the eyes’ slow recovery in response to a flash of bright light at night. In animal research studies, the response rate is measured with electrodes.

Vitamin A Deficiency Keratinization Keratin- hard, insoluble hair & nail protein Keratinization Change in shape & size of epithelial cells due to accumulation of keratin Skin becomes dry, rough, and scaly Fewer and less active goblet cells, so normal digestion and absorption of nutrients from GI tract falters Weakened defenses in epithelial cells of respiratory tract, vagina, inner ear, and urinary tract

Figure 11.6: Vitamin A–Deficiency Symptom—The Rough Skin of Keratinization.

Vitamin A Toxicity Develops when binding proteins are swamped Free vitamin A damages cells Toxicity is a real possibility Preformed vitamin A from animal sources Fortified foods Supplements Children are most vulnerable

β-Carotene Overload β-carotene Found in many excellent fruits and vegetables Excess cannot evolve to Vitamin A toxicity Overconsumption from food harmless β-carotene storage in fat under skin Overconsumption from supplements risky Antioxidant becomes prooxidant, promotes cell division, destroys Vitamin A Most adverse effects for those with heavy EtOH and tobacco use

Figure 11.7: Symptom of Beta-Carotene Excess—Discoloration of the Skin.

Vitamin A Toxicity (Hypervitaminosis A) Bone defects May weaken bones Osteoporosis Overstimulation of osteoclasts Interferes with vitamin D and serum calcium Birth defects Cell death in the spinal cord with >10,000 IU/d before 7th week Vitamin A relatives prescribed for Acne Accutane, topical Retin-A

Accutane Side Effects Ulcerative colitis Crohn’s Disease, Inflammatory Bowel Disease Severe depression, suicidal thoughts Birth defects Liver damage, with nausea, loss of appetite, weight loss, and jaundice Allergic reaction to isotretinoin, resulting in liver disease and other health complications

Vitamin A and Beta-Carotene Recommendations Expressed as retinol activity equivalents (RAE) 1 RAE = 1 µg. retinol 12 µg. β-carotene 3.33 international units (IU’s) Supplements often measured in International Units (IU)

Vitamin A and β-Carotene Food sources Animal sources for Vitamin A Liver (1 oz = 3x RDA), dairy fat, eggs Plant sources for β-Carotene Vitamin A precursors Bioavailability with fat in the same meal Dark green and bright orange fruits and vegetables

β-rich Fruits & Vegetables Apricots, Cantaloupe, Peaches, Persimmon, Mango, Papaya, Purple(on the inside) plums, Watermelon VEGETABLES Beet greens, Bok Choi, Broccoli, Carrots Collards, Dandelion Greens, Kale, Mustard Greens, Pumpkin, Spinach, Sweet Potatoes, Yams, Winter Squash Bold italics mean also C-rich

The carotenoids in foods bring colors to meals; the retinoids in our eyes allow us to see them. p

Vitamin A / β-carotene in Foods

Vitamin D- calciferol Not an essential nutrient Body synthesizes Sunlight Precursor from cholesterol Activation of vitamin D Two hydroxylation reactions Liver adds OH- Kidneys add OH-

Vitamin D Synthesis and Activation

(a precursor made in the liver from cholesterol) In the skin: 7-dehydrocholesterol (a precursor made in the liver from cholesterol) Ultraviolet light from the sun Previtamin D3 Foods (ergocalciferol from plants and cholecalciferol from animals) Vitamin D3 (an inactive form) Hydroxylation In the liver: Figure 11.9: Animated! Vitamin D Synthesis and Activation. The precursor of vitamin D is made in the liver from cholesterol (see Figure 5-11 on p. 147 and Appendix C). The activation of vitamin D is a closely regulated process. The final product, active vitamin D, is also known as 1,25-dihydroxycholecalciferol (or calcitriol). 25-hydroxy vitamin D3 Hydroxylation In the kidneys: 1,25-dihydroxy vitamin D3 (active form) Stepped Art

Vitamin D Roles in the Body Active form of vitamin D is a hormone Binding protein carries it to target organs Ca / P absorption to maintain serum levels Bone growth Ca, Mg, P, Fl absorption preferably from GI Bones resorbed to maintain serum levels Parathyroid hormone, calcitonin, calbindin Other roles Enhances or suppresses gene activity

Vitamin D Deficiency Overt deficiency signs are relatively rare Insufficiency is quite common Contributory factors Dark skin, breastfeeding without supplementation, lack of sunlight, not using fortified milk D deficiency → less calbindin transp. prot.→ low calcium absorption → calcium deficiency→ rob the bones for calcium

Vitamin D Deficiency Rickets in children Osteomalacia (adult rickets) Prevalence >50% Mongolia, Tibet, Netherlands Bones fail to calcify normally, bend when supporting weight Beaded ribs Osteomalacia (adult rickets) Poor mineralization of bones Bones are soft, flexible, brittle, and deformed

Figure 11.10: Vitamin D–Deficiency Symptoms—Bowed Legs and Beaded Ribs of Rickets.

Fontanel A fontanel is an open space in the top of a baby’s skull before the bones have grown together. In rickets, closing of the fontanel is delayed. Anterior fontanel normally closes by the end of the second year. Posterior fontanel normally closes by the end of the first year.

Vitamin D Deficiency Osteoporosis Elderly Loss of calcium from bones Reduced density results in fractures Elderly Vitamin D deficiency is especially likely Skin, liver, kidneys lose ability to make and activate vitamin D Drink less milk Too much time indoors, sunscreen outdoors Drugs that deplete Vitamin D

Vitamin D Deficiency Contributes to Osteoporosis Bone metabolism is influenced by many factors, including vitamin D levels, hormones, genetics, your body weight and your activity levels. Osteoporosis, meaning "porous bones," results from a relative lack of osteoblast activity in comparison to osteoclast activity. Over time, this imbalance leads to a decrease in bone density with a concurrent rise in fracture risk. In adults, vitamin D deficiency leads to a reduction in osteoblast activity, thereby decreasing the rate of bone construction.

National Academy of Science Vitamin D Recommendations In response to concerns that Americans are consuming too little vitamin D, the National Academy of Sciences reviewed its recommendations and offered new guidelines in November 2010. According to the NAS, adults up to age 70 need no more than 600 IU of vitamin D daily to maintain health, and those over 70 need no more than 800 IU. However, many experts, including those at the University of Miami Miller School of Medicine and the University of Toronto, believe that even these recommendations are too low for most age groups and that all elderly adults should receive at least 2,000 IU of vitamin D daily.

Considerations and Recommendations Many of vitamin D's functions, including its influences on immune function and glucose and lipid metabolism, are just beginning to come to light. As new discoveries unfold -- including advances in osteoporosis research – National Academy of Science dietary guidelines for vitamin D may change. Current guidelines reflect an upward adjustment from those devised in 1997, but some researchers still feel these recommendations are inadequate.

Considerations and Recommendations If you are an adult under age 70 who wishes to prevent osteoporosis, your daily vitamin D-3 intake should be at least 600 IU, and if you are older than 70, 800 IU. Consult your physician about the vitamin D-3 dosage that is best for you.

Vitamin D Toxicity Most likely of vitamins to have toxic effects Toxicity raises blood calcium concentrations Forms stones in soft tissues, esp. kidneys May harden blood vessels

Skin Exposure is what it takes to make Vitamin D ↑ What’s the point?

Vitamin D Sources Few food sources Oily (fishy-tasting) fish and egg yolks Fortified milk Sun exposure for 10-20 min (not 2 hrs) per day Dark skin or SPF >8 reduces D synthesis No risk of D toxicity from too much sun Latitude, season, time of day, Overcast, smog, fog

Vitamin D Synthesis and Latitude

Free Radicals

Free Radicals and Disease Free radical damage Contribute to cell damage, disease progression, and aging Polyunsaturated fatty acids in lipoproteins and membranes Alter DNA, RNA, and proteins Illicit inflammatory response

Free Radicals

Free Radicals

Polyunsaturated fatty acids DNA and RNA Proteins Free radical Free radical Free radical Polyunsaturated fatty acids DNA and RNA Proteins Altered DNA and RNA Lipid radicals Altered proteins Absence of specific proteins Excess of specific proteins Impaired cell function Inflammatory response Figure H11.1: Free-Radical Damage. Free radicals are highly reactive. They might attack the polyunsaturated fatty acids in a cell membrane, which generates lipid radicals that damage cells and accelerate disease progression. Free radicals might also attack and damage DNA, RNA, and proteins, which interferes with the body’s ability to maintain normal cell function, causing disease and premature aging. Cell damage Diseases Aging

Free Radical Chain Reaction

Free Radicals and Disease Compound with one or more unpaired electrons Look to steal electron from vulnerable compound Electron-snatching chain reaction Free radical production Degrades or detours normal bodily functions Environmental factors

Vitamin E as Antioxidant

of oxidation processes. Preservatives BHA and BHT are synthetic analogues of vitamin E and operate by reducing oxygen radicals and interrupting the propagation of oxidation processes.

Free Radicals and Disease Body has natural defenses and repair systems Vit. C, β-carotene, Zn, Se, Mn, Cu Not 100 percent effective Less effective with age Oxidative stress Cognition Cancer Heart disease Arthritis and cataracts Diabetes Skin Lungs Accelerates aging

Vitamin E Four different tocopherol compounds Antioxidant Alpha, beta, gamma, and delta Only alpha-tocopherol has vitamin E activity in the body Antioxidant Stop chain reaction of free radicals Protect cells and their membranes Heart disease and cancer

Defending Against Free Radicals System of enzymes against oxidants Copper, selenium, manganese, and zinc Antioxidant vitamins Vitamin E Defends body lipids Beta-carotene Defends lipid membranes Vitamin C Protects other tissues

How Antioxidants defend the body against cancer and CHD Limit free radical formation Neutralize(destroy) free radicals or their precursors Stimulate antioxidant enzyme activity Repair oxidative damage Stimulate repair enzyme activity Support healthy immune system

Defending Against Heart Disease Oxidized LDL fills “foam cells” Accelerate formation of artery-clogging plaques Additional changes in arterial walls Vitamin E protection Supplements Risk of supplement use by those who already have heart disease

Defending Against Cancer Damage to cellular DNA Antioxidants may protect DNA from this damage Inverse relationship with vegetable intake Positive relationship with beef and pork intake Vitamin C as a prooxidant Destruction of cancer cells Vitamin E

Vitamin E Deficiency Primary deficiency is rare Secondary deficiency Fat malabsorption, totally fat-free diet Effects of deficiency Red blood cells break open Erythrocyte hemolysis Neuromuscular dysfunction Other conditions and vitamin E treatment

Vitamin E Toxicity Liver regulates vitamin E concentrations despite intake Toxicity is rare UL is 65 times greater than recommended intake for adults Extremely high doses of vitamin E May interfere with vitamin K activity Thin the blood, increase hemorrhage risk

Vitamin E Recommendations & Foods RDA is based on alpha-tocopherol only U.S. intakes tend to fall short of recommendations Higher requirements for smokers Widespread in foods Destroyed by heat processing and oxidation

Vitamin E in Foods

Foods, Supplements, or Both? Must replenish dietary antioxidants regularly Foods Antioxidants and other valuable nutrients Antioxidant actions of fruits and vegetables are greater than their nutrients alone Supplements Contents, bioavailability Processing Physiological levels vs. pharmacological dose

The Bottom Line on Antioxidants and Disease Prevention (HSPH) Free radicals contribute to chronic diseases from cancer to heart disease and Alzheimer's disease to vision loss. This doesn't automatically mean that substances with antioxidant properties will fix the problem, especially not when they are taken out of their natural context. The studies so far are inconclusive, but generally don't provide strong evidence that antioxidant supplements have a substantial impact on disease. But keep in mind that most of the trials conducted up to now have had fundamental limitations due to their relatively short duration and having been conducted in persons with existing disease.

The Bottom Line on Antioxidants and Disease Prevention (HSPH) That a benefit of beta-carotene on cognitive function was seen in the Physicians' Health Follow-up Study only after 18 years of follow-up is sobering, since no other trial has continued for so long. At the same time, abundant evidence suggests that eating whole fruits, vegetables, and whole grains—all rich in networks of antioxidants and their helper molecules—provides protection against many of these scourges of aging.

Vitamin K Can be obtained from non-food source Bacteria in the GI tract synthesize K Acts primarily in blood clotting K is essential for activating prothrombin Metabolism of bone proteins Osteocalcin binds to bone minerals Low bone density w/out Vit. K and osteocalcin Misc. proteins needing vitamin K in the body

Blood-Clotting Process Calcium and thromboplastin (a phospholipid) from blood platelets Fibrinogen (a soluble protein) Vitamin K Several precursors earlier in the series depend on vitamin K Prothrombin (an inactive protein) Thrombin (an active enzyme) Fibrin (a solid clot) Figure 11.12: Blood-Clotting Process. When blood is exposed to air, foreign substances, or secretions from injured tissues, platelets (small, cell-like structures in the blood) release a phospholipid known as thromboplastin. Thromboplastin catalyzes the conversion of the inactive protein prothrombin to the active enzyme thrombin. Thrombin then catalyzes the conversion of the precursor protein fibrinogen to the active protein fibrin that forms the clot.

Vitamin K Deficiency Primary deficiency is rare Secondary deficiency Fat absorption falters Antibx drugs disrupt vitamin K’s synthesis Anticoagulants have opposite action Newborn infants Sterile intestinal tract Single dose of vitamin K given at birth

Vitamin K Toxicity Not common No UL No adverse effects with high intakes No UL Irregular High doses can reduce effectiveness of anticoagulant drugs, ie. Coumadin

"Vitamin K" by Elson M. Haas M.D. "It is important for the production of many nutrients that we keep our "friendly" colon bacteria active and doing their job; to aid this process we should minimize our use of oral antibiotics, avoid excess sugars and processed foods, and occasionally evaluate and treat any abnormal organisms interfering in our colon, such as yeasts or parasites." "Yogurt, kefir, and acidophilus milk may help to increase the functioning of the intestinal bacterial flora and therefore contribute to vitamin K production."

How much vitamin K can I have each day while on coumadin? Rather than focus on how much vitamin K you should eat, experts say it is more important to keep your vitamin K intake consistent from day to day and not to have drastic changes in amounts of vitamin K-rich foods. For example, if you eat 3 cups of a high-vitamin K food like spinach one day and none the next, this can affect the way your Coumadin works. American Dietetic Association Nutrition Care Manual

Vitamin K – Sources GI tract Food sources Half of person’s need Stored in liver Food sources Green vegetables Vegetable oils

Vitamin K Foods Notable food sources of vitamin K include green vegetables such as collards, spinach, bib lettuce, brussels sprouts, and cabbage and vegetable oils such as soybean oil and canola oil.

The Fat-Soluble Vitamins – In Summary Toxicities are possible Function of fat-soluble vitamins together Vitamins E and A Oxidation, absorption, and storage Vitamins A, D, and K Bone growth and remodeling Vitamins E and K Blood clotting