Hippocrates suggested some 2500 years ago: “Let food be thy medicine and medicine be thy food.”1
In 1996, sales of dietary supplements increased 9% over the previous year and totaled $9.8 billion.2The community has long shown a predilection for taking dietary supplements, and health professionals are increasingly demonstrating a similar trend. Half of the 4501 female physicians aged 30 to 70 years who responded to an American survey took a multivitamin-mineral supplement; 35.5% of them did so regularly.3However, despite a vast array of options (see Table 4-1 and Part Three of this text), no more than 33% took any supplement other than calcium and less than 20% did so regularly.
Given the array of nutritional supplements readily available, the issue has become one of prudent choice.
INDICATIONS FOR SUPPLEMENTATION
Dietary supplements include any substance consumed in addition to the regular diet. Dietary supplements must provide a nutrient that is either being undersupplied to cells or is capable of exerting a pharmacologic effect on cellular processes to be efficacious.4In other words, reasons for dietary supplementation range from an absolute or relatively inadequate dietary intake to use of nutrients and herbs as medications to correct cellular dys- function. In the former, optimal function is achieved when a nutrient required by the organism reaches a specific concentration within the cell.
Low-calorie diets may not deliver the quantity or variety of nutrients necessary for health unless nutrient-dense food is selected. However, during periods of increased physiologic demand (e.g., pregnancy and lac- tation), even normal diets may not supply the increased demand for partic- ular nutrients such as iron or calcium. In the latter instance, when used as medication, the dietary supplement contains a constituent that is either not normally required by the cell or not required in the dose achieved by supplementation. In this case, the supplement may be perceived to act
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TABLE 4-1■Popular Community Remedies SUPPLEMENT/ CONSTITUENTACTIONPOTENTIAL USESIDE EFFECTS Green-lipped musselProstaglandin inhibitor, anti-Rheumatoid arthritisFlatulence, nausea; safe inflammatory effect Green tea/flavonoids, Antioxidant, cancer protective, Reduces risk of cancer and Aggravates bleeding tendency catechinsantimicrobialcardiovascular disease Glucosamine/hexamine Used in synthesis of, e.g., OsteoarthritisConstipation, diarrhea, drowsiness sugarglycoproteins, hyaluronic acid, glucosaminoglycan Shark cartilageGlycosaminoglycans, anti-angio-Osteoarthritis, adjunct cancer Gastrointestinal complaints, hepatitis genesis factorstherapy S-adenosylmethionineMethyl donorDepression, fibromyalgia osteoarthri-Nausea, dry mouth tis, cardiovascular disease Para-aminobenzoic acidB vitamin groupPrevents sunburnRarely rash MelatoninPineal hormoneJet lag, insomniaNil of note, short-term use Flaxseed oil/Lignans, Phytoestrogenic effect, anti-?? Alternative to fish oilNil α-linolenic acid inflammatory (ω-3) Dehydroepiandrosterone Adrenal hormone precursor of Enhances immunity, well-beingSafe but could cause masculin- (DHEA)estrogen & androgens, stimulates ization in females insulin growth factor Chitosan/Binds fat moleculesWeight lossAbsorption of fat-soluble vitamins polysaccharideD, E, C in animals Carnitine/amino acid Long-chain fatty acid transport Adjunct treatment for diseases Nausea, diarrhea, vomiting; derivativeacross membranes, β-oxidation, of atherosclerosisL-carnitine less risk of toxicity transport of acyl coenzyme Athan D-carnitine α-Lipoic acidImproves recycling of other Improves glucose utilization in Occasional skin rash antioxidantsdiabetics Aloe veraHypoglycemia, hypolipidemia, Local application, moisturizer; Occasional allergy antiinflammatoryorally, diabetes
as a drug. If nutritional supplements and herbs are deemed to be drugs, they will be subject to outcome claims and constraints not associated with foods.
LEGISLATIVE STANDARDS: STANDARDIZATION AND SAFETY A major difference between supplements and drugs is in the legislative standards that must be met. In the case of drugs, issues such as adminis- tration of a safe, effective dose need to be meticulously addressed. Safe, effective drug therapy requires at least use of standardized drug formulas in previously determined doses. Although the importance of carefully scru- tinizing the quality of supplements is recognized,5 history suggests that standards need review. Herbal products are not regulated for purity and potency, and batch-to-batch variability is recognized to be associated with varying efficacy and side effects resulting from impurities.6Pharmacologic differences have been reported within a single species of herb (ginseng) cultivated in two different locations.7 The variability of bioactive com- pounds present in different preparations makes it difficult to interpret the efficacy of herbs in analysis of clinical trials. Echinacea products can con- tain other plant extracts, can be derived from different plant species, can be obtained from different parts of the plant, and can be prepared in different ways (e.g., hydrophilic or lipophilic extraction).8Determining the efficacy of garlic from clinical trials has encountered a similar problem. In general, efforts to standardize herbal products are complicated by plant identifica- tion, genetic variation, agronomic factors, the part of the plant used, time and method of harvesting, postharvest handling, manufacturing technique, and stability.9Even the composition of tea leaves depends on the climate, season, horticultural practices, type, and age of the plant.10In addition to not getting the prescribed dose of an active principle, recipients may receive a toxic compound. In late 1989, an epidemic of eosinophilia- myalgia syndrome (several thousand cases) that resulted in 36 deaths in the United States was linked to contamination of a batch of tryptophan manu- factured in Japan.11Nutrient supplement purity may vary with preparation procedures, and chemical variations in plant extracts may result from diverse agricultural practices. Although herbal preparations are more diffi- cult to standardize, nutrients also have a record of not always meeting acceptable standards.
Therapeutic claims carry significant responsibility. If claims are to be made for nutrients and herbs as useful cancer chemotherapeutic agents, they will need to withstand scrutiny equivalent to the standards set for cytotoxic agents being developed for cancer chemoprevention.12 The blueprint for chemotherapy evaluation passes through three phases of rigorous evalua- tion before registration; efficacy, dose toxicity, and long-term side effects are all assessed. The development, evaluation, manufacture, marketing, and prescription of drugs are rigorously regulated.
SUPPLEMENT CLAIMS
By definition, dietary supplements have not been designated drugs. In 1994, the Dietary Supplement Health and Education Act (DSHEA) set up a new framework for Food and Drug Administration (FDA) regulation in the United States.13The DSHEA defined dietary supplements as being neither a replacement for a conventional diet nor a drug. Unlike drugs, supplements are not intended to diagnose, treat, or prevent disease; also, they are not sub- ject to clinical studies to establish their efficacy, safety, appropriate dosage, or potential interactions before marketing. In fact, supplements are consid- ered safe until proven unsafe by the FDA. The DSHEA further broadened the definition for dietary supplements to include, with some exceptions, any product intended for ingestion as a supplement to the diet. Supplements include vitamins, minerals, herbs, botanicals, various other plant-derived substances, amino acids, concentrates, and metabolites.
Supplement manufacturers are permitted to make certain types of claims in the United States. Nutrient-nutrient claims describe the concentration of nutrient in the food. Provided that the supplement contains an adequate concentration of the nutrient, disease-prevention claims are permitted if supplement-disease links have been established (e.g., “folic acid may pre- vent neural tube defects” or “calcium prevents osteoporosis”). Nutrition support claims can also be made. Since October 1999, foods containing at least 6.5 g of soy per serving that are low in fat, saturated fat, and cholesterol are permitted by the FDA to carry the following health claim: “Diets low in saturated fat and cholesterol that include 25 grams of soy protein may reduce the risk of heart disease.”14
The agency reviewed results from 27 studies and concluded that soy pro- tein had demonstrable value for lowering total cholesterol and low-density lipoprotein (LDL) cholesterol levels. Foods must contain (per serving) 6.25 g of soy protein, less than 3 g of fat, less than 1 g of saturated fat, less than 20 mg of cholesterol, and less than 480 mg of sodium in individual food items (less than 720 mg in a main dish and less than 960 mg in a meal) to qualify for the claim. Foods made with the whole soybean, such as tofu, may qual- ify for the claim if they have no fat other than that naturally present in the whole bean. When structure-function claims such as “fiber maintains bowel regularity” are made, a disclaimer stating that the supplement has not been evaluated by the FDA and is not intended to diagnose, treat, cure, or prevent disease must be inserted.
Since 1999, supplements in the United States have also been required to have a “Supplement Facts” label that includes the “reference daily intake”
and a listing of other ingredients including binders, lubricants, coatings, Vitamin, mineral, amino acid, herbal, and botanical supplements are
assumed to be safe until proven unsafe by the FDA.
colorings, and fillers.15Minerals must list their salt source, and herbs must list their common and Latin names. Such labeling reduces, but does not eliminate, the risk of inadvertent consumption of ingredients by sensitive individuals. It also provides useful health information for health-conscious consumers. Results of a cohort study suggest that food labels are useful for helping people reduce fat intake.16
SUPPLEMENT OR FOOD
Regardless of nomenclature gymnastics, it is the performance of the active principle of the nutritional supplement or herb at the active site that deter- mines efficacy. Both fish and fish oils are important sources of essential fatty acids. Essential fatty acids serve as dietary precursors for the formation of eicosanoids. Eicosanoids are powerful autocrine and paracrine regulators of cell and tissue functions ranging from inflammatory reactions, to blood pres- sure regulation, to bronchial and uterine muscle contraction. The risk of car- diovascular and other chronic diseases can be reduced by dietary choice, by supplementation, or by a combination of the two. Eating fish two to three times a week, taking 3 to 4 g of marine oil daily, or taking 1.2 g of long-chain polyunsaturated fat daily—representing 0.5% of total energy—may result in similar wellness outcomes.17However, the comparative efficacy of food ver- sus supplementation is determined by diverse factors. Supplying equivalent concentrations of a nutrient in a food and a supplement does not necessarily or predictably translate into a similar clinical outcome.
Common Considerations
Variables that influence the clinical impact of food and supplements are the concentration, structure, and chemical environment of the nutrient or herb at the active cellular site. The clinical impact of discrepancies in the concentra- tion of a nutrient in various supplements is but one consideration. Calcium carbonate contains around 40% of elemental calcium, and calcium lactate contains around 18%.18 The elemental calcium in a 500-mg tablet of these two products is vastly different. Similarly, 100 mg of zinc gluconate contains 14 mg of zinc, whereas 100 mg of zinc oxide contains 80 mg. Filler adds sub- stantially to the mass of a tablet. The supplement-matrix environment may have health repercussions. Sensitive individuals may fail to appreciate that corn protein may appear on labels as “natural vegetable coating.” Even worse, certain unfortunate individuals may be allergic to the inert matrix used to bulk supplements. Even labeling supplements does not completely
Regardless of whether the initial source is food or a supplement, it is the concentration and configuration of the active principle at the cellular site
that determines the clinical response.
eliminate this hazard. The food-nutrient environment may encounter similar problems. Foods may contain substances to which individuals are aller- gic (e.g., the protein in cow’s milk), or additives used in processing (e.g., monosodium glutamate) may create a risk for sensitive individuals. Before the active principle of a food or supplement can reach the operational site of a cell, it must be absorbed and transported. The concentration of a nutrient that reaches the cell from a meal is enormously influenced by its initial con- centration, digestion, and absorption. This is true regardless of whether the source of the nutrient is food or a supplement.
Transformation of food during preparation, digestion, or metabolism may modify cellular activity and health risk. Food preparation procedures may prevent clinical toxicity. When cassava is soaked and boiled, hydrogen cyanide is leached out into the water and lost to the atmosphere during boil- ing. Peeling potatoes removes chlorogenic acid, an anticarcinogenic sub- stance that binds benzo[a]pyrene, a potential carcinogen found in smoked or barbecued foods. Grilled potatoes should be eaten with their skins. Boiling potatoes causes nutrient losses: 50% of the vitamin C, 25% of the folate, and 40% of the potassium are forfeited. Microwaving and steaming are healthier options. The chemical state of a nutrient affects biologic availability.
Lycopene is the fat-soluble pigment that gives tomatoes, guavas, and water- melon their color. Although these foods are rich in lycopene, food process- ing substantially alters the availability and absorption of this carotenoid.
Lycopene from tomatoes appears more readily in the blood if the tomato is heated and eaten in a meal containing fat. Iron from meat is better absorbed than iron from vegetables. Vitamin C enhances the absorption of iron from vegetable sources, and phytates impair mineral absorption from the bowel.
As with food, the delivery system of nutritional supplements affects absorption. Absorption of calcium from a lactate matrix delivery system is greater than that from a carbonate one. Because the critical factor is the con- centration of the nutrient that reaches the active site within the cell, con- sumption of an equivalent concentration of calcium from diverse sources may have dissimilar outcomes. Prudent nutritional supplement purchasing goes beyond noting the price. It involves reading the label, excluding the presence of allergens, calculating the actual concentration of the desired nutrient in each tablet, and noting associated elements that might influence absorption and metabolism. Although supplements may contain a known quantity and food, a less clearly established concentration of a nutrient, the dose of nutrient that reaches the cell is inevitably unknown. This is due partly to the medium in which the nutrient is ingested and partly to geneti- cally determined physiologic differences between individuals.
Dietary and supplement choices, which result in unique nutrient combi- nations, further contribute to metabolic differences in cellular metabolism.
The impact of diet and dietary supplements on drugs is well recognized.
Patients taking monoamine oxidase inhibitors are advised to avoid aged cheeses and red wine. Patients taking oral contraceptives are prone to vita- min B6deficiency. Supplementation with vitamin B6may precipitate a rela-
tive vitamin B2 deficiency. Similarly, increasing the amounts of particular herbs or foods also requires vigilance. Just as caution is advocated when ginkgo is recommended to patients taking anticoagulants,19so may wariness be necessary when a diet rich in cold water fish is advocated, because this may enhance bleeding time.20
Less well-described than the repercussions of food and supplement inter- actions with drugs are the more subtle interactions of diet with metabolic systems. The cytochrome P-450 enzymes are major catalysts involved in the biotransformation of xenobiotic chemicals and in the metabolism of endoge- nous substrates. P-450 enzymes may be induced or inhibited, and this influ- ences the overall impact on xenobiotic chemicals such as drugs, carcinogens, and pesticides or endogenous chemicals such as steroids, fat-soluble vita- mins, and eicosanoids. Food choices and food preparation procedures fur- ther affect the clinical outcome. Broccoli and cabbage induce certain P-450 enzymes. A key factor in the effectiveness of cruciferous vegetables in cancer prevention appears to be indole-3-carbinol induction of these cytochrome enzymes. Red wine and high-protein diets also enhance P-450 enzyme–
catalyzed oxidation.21A high-protein diet may have clinical repercussion for asthmatic individuals taking theophylline, since protein has been shown to increase metabolism of this drug.
Charbroiled foods such as barbecued beef induce P-450 enzymes. In con- trast, heterocyclic aromatic amines, formed by cooking meat at high temper- atures, may inhibit P-450 enzymes. However, eating potato skins with the meat may reduce absorption of heterocyclic amines. Drinking grapefruit juice, an inhibitor of the intestinal cytochrome P-450 3A4 system, will also modify the overall effect.22 Through the inhibition of an enzyme system responsible for the first-pass metabolism of many medications, grapefruit juice interacts with a variety of medications, leading to elevation of their serum concentrations. Grapefruit juice, through interaction with various members of the cytochrome P-450 enzyme subfamily in the intestinal mucosa, increases the bioavailability of caffeine, 17-β-estradiol and its metabolite estrone, and other substances.23Flavonoids, which are plentiful in plant foods, may directly stimulate or inhibit various P-450 enzyme reac- tions. A barbecue—in which meat and potatoes are cooked over the coals, accompanied by coleslaw and broccoli salad, and washed down with red wine and grapefruit juice—has diverse and complex affects on the P-450 enzyme system.
Genetic constitution provides the template on which metabolic reactions can be influenced by dietary selection or supplementation. Nutrients cause physiologic changes, whether they are consumed in the form of a food or a supplement. A randomized, double-blind, controlled trial demonstrated that administration of 20 mg of beta-carotene daily for 4 weeks significantly decreased the peroxidation products in the breath of smokers.24In this study no significant change in the breath peroxidation products of nonsmokers taking beta-carotene was noted. The clinical impact of supplementation in this study was influenced by more than just the quantity and quality of
the supplement; it was also influenced by the internal environment of the recipient. Smokers have more oxidation products than nonsmokers, and beta-carotene only caused clinically measurable free radical quenching in persons with higher levels of peroxidation. The physiologic condition of the recipient is one variable that should never be overlooked when diet or supplementation is considered as a health-promoting or disease-preventing intervention.
The Case Against Use of Single Supplements
Foods alone and in combination have a profound effect on diverse patho- physiologic processes.25Apples, barley, blackberries, carrots, eggplant, oats, ginger, garlic, ginseng, mushrooms, onions, soybeans, and tea all have a lipid-lowering effect. Lemons, apples, cranberries, garlic, beets, cucumbers, squash, soybeans, cabbage, brussels sprouts, cauliflower, kale, broccoli, and spinach enhance drug detoxification. Licorice, oats, parsley, and ginseng have an anti-inflammatory effect; and garlic, onions, cranberries, and green tea have antimicrobial activity. Oranges, green tea, and garlic are antiprolif- erative; and anise, fennel, soybeans, and cabbage are antiestrogenic.
The variation and interactions of known and unrecognized nutrients in whole foods contribute to nutritional health in diverse, and sometimes unex- pected, ways. This is one reason that “Dietary therapy may not be less costly than drug therapy, when calculated as dollars spent per mmol reduction in LDL, but it should have far-reaching benefits affecting known and suspected risk factors for cardiovascular benefits.”26Nutrients modulate a number of physiologic processes; by providing whole groups of interacting nutrients, foods may achieve far-reaching health benefits.
Groups of antioxidants occur naturally in food. In fact, one explanation for the discrepancy between the health-promoting and protective effects of fruits and vegetables and the inconsistent outcomes of antioxidant supple- ments may be that benefits provided by whole foods result from the inte- grated reductive environment created by plant antioxidants of differing solubility in each of the tissue, cellular, and macromolecular phases.27Water- soluble ascorbate, glutathione, and urate act in concert with lipid-soluble tocopherols and carotenoids and intermediary soluble flavonoids and hydroxycinnamic acids. Dynamic interaction provides the optimal outcome.
Evidence suggests the intake of certain fruits and vegetables can decrease oxidative DNA damage, whereas supplementation with ascorbate, vitamin E, or beta-carotene cannot.28Food may be more effective than supplements.
Although one explanation for the failure of individual nutrients to decrease oxidative DNA damage is loss of the additive effect of antioxidants interacting to maximize their clinical impact, another depends on the chem-
In general, supplementation with a single nutrient carries a greater risk of metabolic imbalance than eating food, a complex nutrient system.