VITAMIN B1 (THIAMIN) HAS A KEY ROLE IN CARBOHYDRATE METABOLISM
Thiamin has a central role in energy-yielding metabolism, and especially the metabolism of carbohydrates (Figure 44–9). Thiamin diphosphate is the coenzyme for three multienzyme complexes that catalyze oxidative decarboxylation reactions: pyruvate dehydrogenase in carbohydrate metabolism (see Chapter 17); α-ketoglutarate dehydrogenase in the citric acid cycle (Chapter 16); and the branched-chain keto-acid dehydrogenase involved in the metabolism of leucine, isoleucine, and valine (see Chapter 29). In each case, the thiamin diphosphate provides a reactive carbon on the thiazole moiety that forms a carbanion, which then adds to the carbonyl group, eg, pyruvate. The addition compound is then decarboxylated, eliminating CO2. Thiamin diphosphate is also the coenzyme for transketolase, in the pentose phosphate pathway (see Chapter 20).
Thiamin, thiamin diphosphate, and the carbanion form.
Thiamin triphosphate has a role in nerve conduction; it phosphorylates, and so activates, a chloride channel in the nerve membrane.
Thiamin Deficiency Affects the Nervous System & the Heart
Thiamin deficiency can result in three distinct syndromes: a chronic peripheral neuritis, beriberi, which may or may not be associated with heart failure and edema; acute pernicious (fulminating) beriberi (shoshin beriberi), in which heart failure and metabolic abnormalities predominate, without peripheral neuritis; and Wernicke encephalopathy with Korsakoff psychosis, which is associated especially with alcohol and narcotic abuse. The role of thiamin diphosphate in pyruvate dehydrogenase means that in deficiency there is impaired conversion of pyruvate to acetyl CoA. In subjects on a relatively high carbohydrate diet, this results in increased plasma concentrations of lactate and pyruvate, which may cause life-threatening lactic acidosis.
Thiamin Nutritional Status Can Be Assessed by Erythrocyte Transketolase Activation
The activation of apo-transketolase (the enzyme protein) in erythrocyte lysate by thiamin diphosphate added in vitro has become the accepted index of thiamin nutritional status.
VITAMIN B2 (RIBOFLAVIN) HAS A CENTRAL ROLE IN ENERGY-YIELDING METABOLISM
Riboflavin provides the reactive moieties of the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) (Figure 44–10). FMN is formed by ATP-dependent phosphorylation of riboflavin; FAD is synthesized by further reaction with ATP in which the AMP moiety is transferred onto FMN. The main dietary sources of riboflavin are milk and dairy products. In addition, because of its intense yellow color, riboflavin is widely used as a food additive.
Riboflavin and the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD).
Flavin Coenzymes Are Electron Carriers in Oxidoreduction Reactions
These include the mitochondrial respiratory chain, key enzymes in fatty acid and amino acid oxidation, and the citric acid cycle. Reoxidation of the reduced flavin in oxygenases and mixed-function oxidases proceeds by way of formation of the flavin radical and flavin hydroperoxide, with the intermediate generation of superoxide and perhydroxyl radicals and hydrogen peroxide. Because of this, flavin oxidases make a significant contribution to the total oxidant stress in the body (see Chapter 45).
Riboflavin Deficiency Is Widespread But Not Fatal
Although riboflavin is centrally involved in lipid and carbohydrate metabolism, and deficiency occurs in many countries, it is not fatal, because there is very efficient conservation of tissue riboflavin. Riboflavin released by the catabolism of enzymes is rapidly incorporated into newly synthesized enzymes. Deficiency is characterized by cheilosis, desquamation and inflammation of the tongue, and a seborrheic dermatitis. Riboflavin nutritional status is assessed by measurement of the activation of erythrocyte glutathione reductase by FAD added in vitro.
NIACIN IS NOT STRICTLY A VITAMIN
Niacin was discovered as a nutrient during studies of pellagra. It is not strictly a vitamin since it can be synthesized in the body from the essential amino acid tryptophan. Two compounds, nicotinic acid and nicotinamide, have the biological activity of niacin; its metabolic function is as the nicotinamide ring of the coenzymes NAD and NADP in oxidation/reduction reactions (Figure 44–11). Some 60 mg of tryptophan is equivalent to 1 mg of dietary niacin. The niacin content of foods is expressed as
Since most of the niacin in cereals is biologically unavailable, this is discounted.
Niacin (nicotinic acid and nicotinamide).
NAD Is the Source of ADP-Ribose
In addition to its coenzyme role, NAD is the source of ADP-ribose for the ADP-ribosylation of proteins and polyADP-ribosylation of nucleoproteins involved in the DNA repair mechanism. Cyclic ADP-ribose and nicotinic acid adenine dinucleotide, formed from NAD, act to increase intracellular calcium in response to neurotransmitters and hormones.
Pellagra Is Caused by Deficiency of Tryptophan & Niacin
Pellagra is characterized by a photosensitive dermatitis. As the condition progresses, there is dementia and possibly diarrhea. Untreated pellagra is fatal. Although the nutritional etiology of pellagra is well established, and either tryptophan or niacin prevents or cures the disease, additional factors, including deficiency of riboflavin or vitamin B6, both of which are required for synthesis of nicotinamide from tryptophan, may be important. In most outbreaks of pellagra, twice as many women as men are affected, probably the result of inhibition of tryptophan metabolism by estrogen metabolites.
Pellagra Can Occur as a Result of Disease Despite an Adequate Intake of Tryptophan & Niacin
A number of genetic diseases that result in defects of tryptophan metabolism are associated with the development of pellagra, despite an apparently adequate intake of both tryptophan and niacin. Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan, resulting in large losses as a result of intestinal malabsorption and failure of renal reabsorption. In carcinoid syndrome, there is metastasis of a primary liver tumor of enterochromaffin cells, which synthesize 5-hydroxytryptamine. Overproduction of 5-hydroxytryptamine may account for as much as 60% of the body’s tryptophan metabolism, causing pellagra because of the diversion away from NAD synthesis.
Niacin Is Toxic in Excess
Nicotinic acid has been used to treat hyperlipidemia when of the order of 1-6 g/d are required, causing dilatation of blood vessels and flushing, along with skin irritation. Intakes of both nicotinic acid and nicotinamide in excess of 500 mg/d also cause liver damage.
VITAMIN B6 IS IMPORTANT IN AMINO ACID & GLYCOGEN METABOLISM & IN STEROID HORMONE ACTION
Six compounds have vitamin B6 activity (Figure 44–12): pyridoxine, pyridoxal, pyridoxamine, and their 5′-phosphates. The active coenzyme is pyridoxal 5′-phosphate. Some 80% of the body’s total vitamin B6 is pyridoxal phosphate in muscle, mostly associated with glycogen phosphorylase. This is not available in deficiency, but is released in starvation, when glycogen reserves become depleted, and is then available, especially to liver and kidney, to meet increased requirement for gluconeogenesis from amino acids.
Interconversion of the vitamin B6 vitamers.
Vitamin B6 Has Several Roles in Metabolism
Pyridoxal phosphate is a coenzyme for many enzymes involved in amino acid metabolism, especially transamination and decarboxylation. It is also the cofactor of glycogen phosphorylase, where the phosphate group is catalytically important. In addition, B6 is important in steroid hormone action. Pyridoxal phosphate removes the hormone-receptor complex from DNA binding, terminating the action of the hormones. In vitamin B6 deficiency, there is increased sensitivity to the actions of low concentrations of estrogens, androgens, cortisol, and vitamin D.
Vitamin B6 Deficiency Is Rare
Although clinical deficiency disease is rare, there is evidence that a significant proportion of the population have marginal vitamin B6 status. Moderate deficiency results in abnormalities of tryptophan and methionine metabolism. Increased sensitivity to steroid hormone action may be important in the development of hormone-dependent cancer of the breast, uterus, and prostate, and vitamin B6 status may affect the prognosis.
Vitamin B6 Status Is Assessed by Assaying Erythrocyte Transaminases
The most widely used method of assessing vitamin B6 status is by the activation of erythrocyte transaminases by pyridoxal phosphate added in vitro, expressed as the activation coefficient. Measurement of plasma concentrations of the vitamin are also used.
In Excess, Vitamin B6 Causes Sensory Neuropathy
The development of sensory neuropathy has been reported in patients taking 2 to 7 g of pyridoxine per day for a variety of reasons (there is some slight evidence that it is effective in treating premenstrual syndrome). There was some residual damage after withdrawal of these high doses; other reports suggest that intakes in excess of 100 to 200 mg/d are associated with neurological damage.
VITAMIN B12 IS FOUND ONLY IN FOODS OF ANIMAL ORIGIN
The term “vitamin B12” is used as a generic descriptor for the cobalamins—those corrinoids (cobalt-containing compounds possessing the corrin ring) having the biologic activity of the vitamin (Figure 44–13). Some corrinoids that are growth factors for microorganisms not only have no vitamin B12 activity, but may also be antimetabolites of the vitamin. Although it is synthesized exclusively by microorganisms, for practical purposes vitamin B12 is found only in foods of animal origin, there being no plant sources of this vitamin. This means that strict vegetarians (vegans) are at risk of developing B12 deficiency. The small amounts of the vitamin formed by bacteria on the surface of fruits may be adequate to meet requirements, but preparations of vitamin B12 made by bacterial fermentation are available.
Vitamin B12. Four coordination sites on the central cobalt atom are chelated by the nitrogen atoms of the corrin ring, and one by the nitrogen of the dimethylbenzimidazole nucleotide. The sixth coordination site may be occupied by: CN− (cyanocobalamin), OH− (hydroxocobalamin), H2O (aquocobalamin, —CH3 (methyl cobalamin), or 5′-deoxyadenosine (adenosylcobalamin).
Vitamin B12 Absorption Requires Two Binding Proteins
Vitamin B12 is absorbed bound to intrinsic factor, a small glycoprotein secreted by the parietal cells of the gastric mucosa. Gastric acid and pepsin release the vitamin from protein binding in food and make it available to bind to cobalophilin, a binding protein secreted in the saliva. In the duodenum, cobalophilin is hydrolyzed, releasing the vitamin for binding to intrinsic factor. Pancreatic insufficiency can therefore be a factor in the development of vitamin B12 deficiency, resulting in the excretion of cobalophilin-bound vitamin B12. Intrinsic factor binds only the active vitamin B12 vitamers and not other corrinoids. Vitamin B12 is absorbed from the distal third of the ileum via receptors that bind the intrinsic factor-vitamin B12 complex, but not free intrinsic factor or free vitamin. There is considerable enterohepatic circulation of vitamin B12, with excretion in the bile, then reabsorption after binding to intrinsic factor in the ileum.
There Are Two Vitamin B12–Dependent Enzymes
Methylmalonyl CoA mutase, and methionine synthase (Figure 44–14) are vitamin B12-dependent enzymes. Methylmalonyl CoA is formed as an intermediate in the catabolism of valine and by the carboxylation of propionyl CoA arising in the catabolism of isoleucine, cholesterol, and rare fatty acids with an odd number of carbon atoms, or directly from propionate, a major product of microbial fermentation in the rumen. It undergoes a vitamin B12-dependent rearrangement to succinyl CoA, catalyzed by methylmalonyl CoA mutase (see Figure 19–2). The activity of this enzyme is greatly reduced in vitamin B12 deficiency, leading to an accumulation of methylmalonyl CoA and urinary excretion of methylmalonic acid, which provides a means of assessing vitamin B12 nutritional status.
Homocysteine and the “folate trap. Vitamin B12 deficiency leads to impairment of methionine synthase, resulting in accumulation of homocysteine and trapping folate as methyltetrahydrofolate.
Vitamin B12 Deficiency Causes Pernicious Anemia
Pernicious anemia arises when vitamin B12 deficiency impairs the metabolism of folic acid, leading to functional folate deficiency that disturbs erythropoiesis, causing immature precursors of erythrocytes to be released into the circulation (megaloblastic anemia). The most common cause of pernicious anemia is failure of the absorption of vitamin B12 rather than dietary deficiency. This can be the result of failure of intrinsic factor secretion caused by autoimmune disease affecting parietal cells or from production of anti-intrinsic factor antibodies. There is irreversible degeneration of the spinal cord in pernicious anemia, as a result of failure of methylation of one arginine residue in myelin basic protein. This is the result of methionine deficiency in the central nervous system, rather than secondary folate deficiency.
THERE ARE MULTIPLE FORMS OF FOLATE IN THE DIET
The active form of folic acid (pteroyl glutamate) is tetrahydrofolate (Figure 44–15). The folates in foods may have up to seven additional glutamate residues linked by γ-peptide bonds. In addition, all of the one-carbon substituted folates in Figure 44–15 may also be present in foods. The extent to which the different forms of folate can be absorbed varies, and folate intakes are calculated as dietary folate equivalents—the sum of μg food folates + 1.7 × μg of folic acid (used in food enrichment).
Tetrahydrofolic acid and the one-carbon substituted folates.
Tetrahydrofolate Is a Carrier of One-Carbon Units
Tetrahydrofolate can carry one-carbon fragments attached to N-5 (formyl, formimino, or methyl groups), N-10 (formyl) or bridging N-5–N-10 (methylene or methenyl groups). 5-Formyl-tetrahydrofolate is more stable than folate and is therefore used pharmaceutically (known as folinic acid), and the synthetic (racemic) compound (leucovorin). The major point of entry for one-carbon fragments into substituted folates is methylene-tetrahydrofolate (Figure 44–16), which is formed by the reaction of glycine, serine, and choline with tetrahydrofolate. Serine is the most important source of substituted folates for biosynthetic reactions, and the activity of serine hydroxymethyltransferase is regulated by the state of folate substitution and the availability of folate. The reaction is reversible, and in liver it can form serine from glycine as a substrate for gluconeogenesis. Methylene-, methenyl-, and 10-formyl-tetrahydrofolates are interconvertible. When one-carbon folates are not required, the oxidation of formyl-tetrahydrofolate to yield carbon dioxide provides a means of maintaining a pool of free folate.
Sources and utilization of one-carbon substituted folates.
Inhibitors of Folate Metabolism Provide Cancer Chemotherapy, Antibacterial, & Antimalarial Drugs
The methylation of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (TMP), catalyzed by thymidylate synthase, is essential for the synthesis of DNA. The one-carbon fragment of methylene-tetrahydrofolate is reduced to a methyl group with release of dihydrofolate, which is then reduced back to tetrahydrofolate by dihydrofolate reductase. Thymidylate synthase and dihydrofolate reductase are especially active in tissues with a high rate of cell division. Methotrexate, an analog of 10-methyl-tetrahydrofolate, inhibits dihydrofolate reductase and has been exploited as an anticancer drug. The dihydrofolate reductases of some bacteria and parasites differ from the human enzyme; inhibitors of these enzymes can be used as antibacterial drugs (eg, trimethoprim) and antimalarial drugs (eg, pyrimethamine).
Vitamin B12 Deficiency Causes Functional Folate Deficiency—the “Folate Trap”
When acting as a methyl donor, S-adenosyl methionine forms homocysteine, which may be remethylated by methyl-tetrahydrofolate catalyzed by methionine synthase, a vitamin B12–dependent enzyme (Figure 44–14). As the reduction of methylene-tetrahydrofolate to methyl-tetrahydrofolate is irreversible and the major source of tetrahydrofolate for tissues is methyltetrahydrofolate, the role of methionine synthase is vital, and provides a link between the functions of folate and vitamin B12. Impairment of methionine synthase in vitamin B12 deficiency results in the accumulation of methyltetrahydrofolate that cannot be used — the “folate trap.” There is therefore functional deficiency of folate, secondary to the deficiency of vitamin B12.
Folate Deficiency Causes Megaloblastic Anemia
Deficiency of folic acid itself or deficiency of vitamin B12, which leads to functional folic acid deficiency, affects cells that are dividing rapidly because they have a large requirement for thymidine for DNA synthesis. Clinically, this affects the bone marrow, leading to megaloblastic anemia.
Folic Acid Supplements Reduce the Risk of Neural Tube Defects & Hyperhomocysteinemia, & May Reduce the Incidence of Cardiovascular Disease & Some Cancers
Supplements of 400 μg/d of folate begun before conception result in a significant reduction in the incidence of spina bifida and other neural tube defects. Because of this, there is mandatory enrichment of flour with folic acid in many countries. Elevated blood homocysteine is a significant risk factor for atherosclerosis, thrombosis, and hypertension. The condition is the result of an impaired ability to form methyltetrahydrofolate by methylene-tetrahydrofolate reductase, causing functional folate deficiency, resulting in failure to remethylate homocysteine to methionine. People with an abnormal variant of methylene-tetrahydrofolate reductase that occurs in 5% to 10% of the population do not develop hyperhomocysteinemia if they have a relatively high intake of folate. A number of placebo-controlled trials of supplements of folate (commonly together with vitamins B6 and B12) have shown the expected lowering of plasma homocysteine, but apart from reduced incidence of stroke there has been no effect on death from cardiovascular disease.
There is also evidence that low folate status results in impaired methylation of CpG islands in DNA, which is a factor in the development of colorectal and other cancers. A number of studies suggest that folic acid supplementation or food enrichment may reduce the risk of developing some cancers. However, there is also some evidence that folate supplements increase the rate of transformation of preneoplastic colorectal polyps into cancers, so that people with such polyps may be at increased risk of developing colorectal cancer if they have a high folate intake.
Folic Acid Enrichment of Foods May Put Some People at Risk
Folic acid supplements will rectify the megaloblastic anemia of vitamin B12 deficiency but not the irreversible nerve damage seen in vitamin B12 deficiency. A high intake of folic acid can thus mask vitamin B12 deficiency. This is especially a problem for elderly people, since atrophic gastritis that develops with increasing age leads to failure of gastric acid secretion, and hence failure to release vitamin B12 from dietary proteins. Because of this, although many countries have adopted mandatory enrichment of flour with folic acid to prevent neural tube defects, others have not. There is also antagonism between folic acid and some anticonvulsants used in the treatment of epilepsy, and, as noted above, there is some evidence that folate supplements may increase the risk of developing colorectal cancer among people with preneoplastic colorectal polyps.
DIETARY BIOTIN DEFICIENCY IS UNKNOWN
The structures of biotin, biocytin, and carboxybiotin (the active metabolic intermediate) are shown in Figure 44–17. Biotin is widely distributed in many foods as biocytin (ε-amino-biotinyllysine), which is released on proteolysis. It is synthesized by intestinal flora in excess of requirements. Deficiency is unknown, except among people maintained for many months on total parenteral nutrition, and a very small number who eat abnormally large amounts of uncooked egg white, which contains avidin, a protein that binds biotin and renders it unavailable for absorption.
Biotin, biocytin, and carboxy-biocytin.
Biotin Is a Coenzyme of Carboxylase Enzymes
Biotin functions to transfer carbon dioxide in a small number of reactions: acetyl-CoA carboxylase (see Figure 23–1), pyruvate carboxylase (Figure 19–1), propionyl-CoA carboxylase (see Figure 19–2), and methylcrotonyl-CoA carboxylase. A holocarboxylase synthetase catalyzes the transfer of biotin onto a lysine residue of the apo-enzyme to form the biocytin residue of the holoenzyme. The reactive intermediate is 1-N-carboxybiocytin, formed from bicarbonate in an ATP-dependent reaction. The carboxyl group is then transferred to the substrate for carboxylation.
Biotin also has a role in regulation of the cell cycle, acting to biotinylate key nuclear proteins.
AS PART OF CoA & ACP, PANTOTHENIC ACID ACTS AS A CARRIER OF ACYL GROUPS
Pantothenic acid has a central role in acyl group metabolism when acting as the pantetheine functional moiety of coenzyme A or acyl carrier protein (ACP) (Figure 44–18). The pantetheine moiety is formed after combination of pantothenate with cysteine, which provides the—SH prosthetic group of CoA and ACP. CoA takes part in reactions of the citric acid cycle (see Chapter 16), fatty acid oxidation (see Chapter 22), acetylations, and cholesterol synthesis (Chapter 26). ACP participates in fatty acid synthesis (see Chapter 23). The vitamin is widely distributed in all food-stuffs, and deficiency has not been unequivocally reported in humans except in specific depletion studies.
Pantothenic acid and coenzyme A. Asterisk shows site of acylation by fatty acids.
ASCORBIC ACID IS A VITAMIN FOR ONLY SOME SPECIES
Vitamin C (Figure 44–19) is a vitamin for human beings and other primates, the guinea pig, bats, passeriform birds, and most fishes and invertebrates; other animals synthesize it as an intermediate in the uronic acid pathway of glucose metabolism (see Figure 20–4). In those species for which it is a vitamin, there is a block in the pathway as a result of the absence of gulonolactone oxidase. Both ascorbic acid and dehydroascorbic acid have vitamin activity.
Vitamin C Is the Coenzyme for Two Groups of Hydroxylases
Ascorbic acid has specific roles in the copper-containing hydroxylases and the α-ketoglutarate-linked iron-containing hydroxylases. It also increases the activity of a number of other enzymes in vitro, although this is a nonspecific reducing action. In addition, it has a number of nonenzymic effects as a result of its action as a reducing agent and oxygen radical quencher (see Chapter 45).
Dopamine β-hydroxylase is a copper-containing enzyme involved in the synthesis of the catecholamines (norepinephrine and epinephrine), from tyrosine in the adrenal medulla and central nervous system. During hydroxylation the Cu+ is oxidized to Cu2+; reduction back to Cu+ specifically requires ascorbate, which is oxidized to monodehydroascorbate.
A number of peptide hormones have a carboxy terminal amide that is derived from a terminal glycine residue. This glycine is hydroxylated on the α-carbon by a copper-containing enzyme, peptidylglycine hydroxylase, which, again, requires ascorbate for reduction of Cu2+.
A number of iron-containing, ascorbate-requiring hydroxylases share a common reaction mechanism, in which hydroxylation of the substrate is linked to oxidative decarboxylation of α-ketoglutarate. Many of these enzymes are involved in the modification of precursor proteins. Proline and lysine hydroxylases are required for the postsynthetic modification of procollagen to collagen, and proline hydroxylase is also required in formation of osteocalcin and the C1q component of complement. Aspartate β-hydroxylase is required for the postsynthetic modification of the precursor of protein C, the vitamin K-dependent protease that hydrolyzes activated factor V in the blood-clotting cascade (see Chapter 52). Trimethyllysine and γ-butyrobetaine hydroxylases are required for the synthesis of carnitine.
Vitamin C Deficiency Causes Scurvy
Signs of vitamin C deficiency include skin changes, fragility of blood capillaries, gum decay, tooth loss, and bone fracture, many of which can be attributed to deficient collagen synthesis.
There May Be Benefits from Higher Intakes of Vitamin C
At intakes above about 100 mg/d, the body’s capacity to metabolize vitamin C is saturated, and any further intake is excreted in the urine. However, in addition to its other roles, vitamin C enhances the absorption of inorganic iron, and this depends on the presence of the vitamin in the gut. Therefore, increased intakes may be beneficial. There is very little good evidence that high doses of vitamin C prevent the common cold, although they may reduce the duration and severity of symptoms.
MINERALS ARE REQUIRED FOR BOTH PHYSIOLOGIC & BIOCHEMICAL FUNCTIONS
Many of the essential minerals (Table 44–6) are widely distributed in foods, and most people eating a mixed diet are likely to receive adequate intakes. The amounts required vary from grams per day for sodium and calcium, through milligrams per day (eg, iron and zinc), to micrograms per day for the trace elements. In general, mineral deficiencies occur when foods come from one region where the soil may be deficient in some minerals (eg, iodine and selenium, deficiencies of both of which occur in many areas of the world). When foods come from a variety of regions, mineral deficiency is less likely to occur. Iron deficiency is an important problem worldwide, because if iron losses from the body are relatively high (eg, from heavy menstrual blood loss or intestinal parasites), it is difficult to achieve an adequate intake to replace losses. However, 10% of the population (and more in some areas) are genetically at risk of iron overload, leading to formation of free radicals as a result of nonenzymic reactions of iron ions in free solution when the capacity of iron binding proteins has been exceeded. Foods grown on soil containing high levels of selenium cause toxicity, and excessive intakes of sodium cause hypertension in susceptible people.
TABLE 44–6Classification of Minerals According to Their Function ||Download (.pdf) TABLE 44–6 Classification of Minerals According to Their Function
|Function ||Mineral |
|Structural function ||Calcium, magnesium, phosphate |
|Involved in membrane function ||Sodium, potassium |
|Function as prosthetic groups in enzymes ||Cobalt, copper, iron, molybdenum, selenium, zinc |
|Regulatory role or role in hormone action ||Calcium, chromium, iodine, magnesium, manganese, sodium, potassium |
|Known to be essential, but function unknown ||Silicon, vanadium, nickel, tin |
|Have effects in the body, but essentiality is not established ||Fluoride, lithium |
|May occur in foods and known to be toxic in excess ||Aluminum, arsenic, antimony, boron, bromine, cadmium, cesium, germanium, lead, mercury, silver, strontium |