Other Substances in Food
Several substances naturally present in foods are known to be required in the diets of various animal or microbial species, but there is little or no evidence of their dietary essentiality for humans. Because it is possible that some of the compounds within these classes of substances may eventually be shown to be needed in the diets of humans, and thus may one day be candidates for RDAs, they are included in this chapter.
Foods contain literally thousands of organic substances presumed to have a biological function in the plant or animal from which the food is derived or which are by-products of the plant's or animal's metabolism. Most of these substances can be synthesized in the human body in adequat amounts to meet biological needs and, thus, are not essential dietary nutrients. Examples include fatty acids, such as oleic, stearic, and palmitic acids; glycerol; free nonessential amino acids, such as glycine, alanine, aspartic acid, and glutamic acid; glucose and various less common sugars, such as pentoses and galactose; and derivatives and polymers of sugars.
Many inorganic elements that are not essential for humans enter the diet through foods of vegetable origin, either because they are essential for the plants or through nonspecific absorpttion from the soil. Indeed, most of the inorganic elements of the periodic table are present in foods and drinking water, usually in trace amounts. Some elements may occur in amounts that may be toxic under certain conditions. Inorganic elements in foods that have no accepted biological function in animals or humans are aluminum, antimony, barium, beryllium, gallium, germanium, gold, mercury, rare earth minerals, silver, strontium, thallium, and titanium.
Natural foods contain many compounds that have no known nutritional effects. These include the flavonoids, rutin, quercetin, and hesperidinthe so-called vitamin P factors (Herbert, 1988)and the proposed vitamin Q (Quick, 1975). Some of these naturally occurring compounds (e.g., caffeine in coffee and chocolate) have pharmacological effects.
NUTRIENTS ESSENTIAL FOR SOME HIGHER ANIMALS BUT NOT PROVED TO BE REQUIRED BY NORMAL HUMANS
Choline has been known to be present in mammalian tissues since it was first discovered and isolated from hog bile in 1862 (Strecker, 1862). It can be biosynthesized from ethanolamine and methyl groups derived from methionine, but it is likely that most tissue choline is derived from dietary phosphatides. Although choline is found in nature as the free compound, it has no known functions, except as a constituent of larger molecules (Kuksis and Mookerjea, 1984). As a component of phosphatidylcholine (lecithin), it is important to the structure of all cell memnbranes, plasma lipoproteins, and pulmonary surfactant (Kuksis and Mookerjea, 1984; Zeisel, 1981). In the central nervous system, it functions as a structural constituent of sphingomyelin and as a component of the neurotransmitter acetylcholine (Zeisel, 198 1).
Choline is a dietary requirement of several animal species, including the dog, cat, rat, and guinea pig; however, it has not been shown to be essential for humans. Choline is found in a wide range of plant and animal foods. For example, eggs, liver, and soybeans are rich in lecithin, whereas free choline is found in such vegetables as cauliflower and lettuce (Wurtman, 1979). Lecithins are used as an emulsifying agent in foods such as chocolate or margarine. An average daily intake of choline is about 400 to 900 mg.
The oral administration of choline as choline chloride (2 to 5 g) or lecithin (100 to 15 g) will elevate plasma choline concentrations from 10 to 40 µmol (Jope et al., 1982; Zeisel, 1981). Large doses of dietary choline increase the level of the neurotransmitter acetylcholine, which may be deficient in certain neurological diseases, especially in the elderly (Zeisel, 1988).
The possibility that alcoholic cirrhosis results in part from inadequate dietary choline has been investigated (Baraona and Lieber, 1979). However, it is uncertain whether the liver damage is due to
the toxic effect of the alcohol itself or to the alcohol in combination with deficiency of several nutritional factors (Kuksis and Mookerjea, 1984).
Both de novo synthesis and active transport of' choline have been demonstrated in the placenta (Welsch, 1978). The demand for choline-containing compounds is high during growth and development, and may exceed synthetic capacity in the human newborn (Zeisel, 1981). It is likely that the neonate needs a dietary supply of choline, but the point is not yet firmly established. The American Academy of Pediatrics (AAP, 1985) has, however, recommended that infant formula contain 7 mg of choline per 100 kcal. This is based on the amount of choline in human milk, which also provides choline as phosphatidylcholine and sphingomyelin.
Taurine (ß-aminoethanesulfonic acid) is an important component of a wide range of metabolic activities in many tissues and is essential to the formation of conjugated forms of taurine (bile salts) present in bile. Deficiencies have been produced in young monkeys, felines, and other laboratory animals. It is not generally considered an essential nutrient for humans under normal physiological conditions, since it can be synthesized from dietary cysteine or methionine (Hayes, 1985). There is concern, however, that formula-fed infants may be at greater risk of taurine insufficiency than breastfed infants, because formulas based on cow's milk contain much lower levels of taurine than does human milk, i.e., 1 to 3 µmol/100 ml compared with 26 to 35 µmol/100 ml. Indeed, lower urine and plasma levels of taurine have been observed in premature infants fed formulas based on cow's milk than in breastfed infants (Sturman, 1988).
For full-term infants, differences in plasma and urine levels were also observed between those fed human milk and those fed taurinedeficient formulas (Gaull, 1982; Järvenpää et al., 1982). Yet, whether taurine is a dietary essential nutrient remains equivocal, since even in the premature infant, taurine supplementation did not produce changes in growth, nitrogen retention, or general metabolism (Järvenpää et al., 1983; Okamoto et al., 1984).
Because the essentiality of dietary taurine for infants has not been fully established, no RDA can be established at this time. For recent general reviews on taurine, see Chapman and Greenwood (1988), Chesney (1987), Sturman (1988), and Wright et al. (1986).
Carnitine is required metabolically for the transport of long-chain fatty acids into the matrix of the mitochondriathe site of ß-oxidation. It therefore plays a critical role in energy metabolism. Carnitine is synthesized in the liver and kidney of the adult from the essential amino acids lysine and methionine (Broquist and Borum, 1982). Although the well-nourished adult can probably synthesize adequate amounts of carnitine, the newborn infant appears to have reduced stores of carnitine as well as a low capacity for synthesizing it. Human milk contains approximately 50 to 100 nmol/ml of carnitine. However, infants fed soy formulas or maintained on total parenteral nutrition receive no exogenous carnitine and have been shown to have plasma carnitine concentrations lower than those of infants fed human milk (Borum, 1983; Olson et al., 1989). A critical question that must be answered is whether these decreased carnitine concentrations have demonstrable functional consequences. Several laboratories are investigating the possibility that carnitine may be an essential nutrient for the newborn, especially for those born prematurely.
Animal products are the best dietary sources of carnitine. As a general rule, the redder the meat, the higher the carnitine concentration. Dairy products contain carnitine predominantly in the whey fraction (Borum, 1983, 1986).
Human carnitine deficiency was first described in 1973 (Engel and Angelini, 1973). Since then, more than a hundred people have been diagnosed as having genetic carnitine deficiency. The biochemical mechanism causing the carnitine deficiency has not been adequately identified in any patient. Deficiency of this substance appears to be characterized by a family of syndromes with a broad range of signs and symptoms that include progressive muscle weakness with lipid infiltration of the skeletal muscle and reduced muscle carnitine concentration, cardiomyopathy, severe hypoglycemia, elevated blood ammonia concentrations, and reduced ability to increase ketogenesis on fasting. Carnitine deficiency can also occur in conjunction with a variety of other conditions, such as organic aciduria, or with chronic hemodialysis of renal patients, long-term total parenteral nutrition, and treatment with valproic acid. Supplementation of carnitine-deficient patients with L-carnitine reduces symptoms in some but not all of the subjects (Borum, 1983, 1986; Bowyer et al., 1989). For representative recent reviews on carnitine, see Borum (1986), Carroll et al. (1987), Feller and Rudman (1988), and Rebouche (1986).
Carnitine was originally referred to as vitamin B because of its essentiality for the mealworm Tenebrio molitor. However, it has not been demonstrated to be a vitamin for the healthy adult human (Borum, 1983, 1986), and no RDA can be established at this time.
Myo-inositol is a cyclic alcohol (cyclohexanehexol) closely related chemically to glucose. Of the nine inositol isomers, only myo-inositol is of importance in plant and animal metabolism. It is found in plants, usually as phytic acid, and in animal tissues, primarily as a constituent of phospholipids in biomembranes (Holub, 1982). Consideration of myo-inositol as an essential nutrient is increasing because of the recent dliscovery that myo-inositol trisphosphate is a second messenger for receptor-mediated hormonal stimuli for mobilizing intracellular calcium (Berridge and Irvine, 1984). In addition, myo-inositol appears to have a lipotropic action that may originate from its vital role as a substrate for the biosynthesis of phosphatidyl inositol and polyphosphoinositides, which are essential components of biomembranes (Holub, 1982). The myo-inositol content of tissues is provided by the diet and through biosynthesis (Lewin and Beer, 1973; Middleton and Setchell, 1972). Dietary myo-inositol has not been shown to produce any known deleterious effect to any organ system when given in generous amounts (larger than present in normal diets). For a comprehensive account of the biological importance of myo-inositol, the reader is referred to see Agranoff (1986) and Prentki and Matschinsky (1987).
Although dietary essentiality has not been shown for humans, female gerbils have been shown to require myo-inositol in their diets (Hegsted et al., 1973, 1974). Deficiency is characterized by intestinal lipodystrophy (Chu and Gever, 1983). In rats, myo-inositol deficiency has been reported to produce triglyceride accumulation and abnormal fatty acid metabolism. These studies have been summarized by Holub (1982). Altered myo-inositol levels have been found in rats, rabbits, and other animals with diabetes mellitus, chronic renal failure, or galactosemia, and a possible therapeutic role for myo-inositol has been suggested. In particular, restoration of nerve conduction velocity has been demonstrated in patients with dialetic neuropathy following the addition of myo-inositol to their diets (Greene et al., 1975; Mayer and Tomlinson, 1983; Winegrad and Greene, 1976). The importance of these studies for normal humans has not been established, so no RDA for myo-inositol can be established.
Evidence for the essentiality of trace elements in humans is often difficult to obtain directly; it can be reliably predicted from proven essentiality in other mammalian species and from identification of certain elements as part of normal human enzyme systems. Evidence for a requirement in laboratory animals has been presented for many of the elements discussed below (especially arsenic, boron, nickel, and silicon), but in most cases the requirement has not been quantified. Deficiency in humans has not been established for any of these trace elements. Hence, there are no data from which a human requirement could be estimated and no provisional allowance can be given.
Arsenic, Nickel, Silicon, and Boron
There is substantial evidence to establish the essentiality of these trace elements in animals (Nielsen, 1988). Arsenic deficiency depresses growth and impairs reproduction in rats, minipigs, chickens, and goats. Nickel deficiency results in decreased growth in rats, sheep, cows, goats, and minipigs, and depressed hematopoiesis has been observed in rats, sheep, cows, and goats. Silicon deficiency leads to structural abnormalities of the long bones and skull in chickens (Carlisle, 1972; Schwarz and Milne, 1972). It apparently is involved in the normal growth of bone more through the mineralization process than through the formation of the organic matrix.
Boron deficiency has been reported in studies in rats, chickens, and humans (Nielsen, 1988; Nielsen et al., 1987). Boron appears to affect calcium and magnesium metabolism and may be needed for membrane function. Boron deficiency signs may be related to the level of vitamin D and possibly other nutrients in the diet. Boron has long been known to be essential for the growth of most plants.
Cadmium, Lead, Lithium, Tin, and Vanadium
Depressed growth, impaired reproductive performance, and other changes have been reported in laboratory animals fed diets extremely low in these elements and kept in an environment allowing the strictest control of contamination (Nielsen, 1988). Nutritional requirements, if they exist, are very low and easily met by the levels naturally occurring in foods, water, and air. The evidence for requirements and essentiality is weak.
The only known nutritional, but very vital, function of cobalt is as an integral part of vitamin B12. Because all vitamin B, is derived from bacterial synthesis, inorganic cobalt can be considered
essential for animal species that depend totally on their bacterial flora for their vitamin B.,. This is the case for ruminant animal species in whom cobalt deficiency is well known; it might also have some relevance for strict vegetarians whose intake of the preformed vitamin is severely limited. However, there is no evidence that the intake of cobalt is ever limiting in the human diet, and no RDA is necessary.
GROWTH FACTORS AND COENZYMES
Various unidentified growth factors for several animal species, including infants, are known to exist in foods, but their role, if any, in normal nutrition is unknown (Berseth, 1987; Cheeke and Patton, 1978; Jaeger et al., 1987; Lofgren et al., 1974; Weaver et al., 1987).
Recently, there has been considerable interest in possible nutritional effects of compounds known to be important coenzymes, or related to them. Several polyamines, including spermine and spermidine, are required for the growth of normal and neoplastic cells (Celano et al., 1988) and for the induction of intestinal maturation in the rat (Dufour et al., 1988). Several recent studies have shown various immunologic suppression and metabolic effects of several dietary nucleotides in human infants and laboratory animals (DeLucchi et al., 1987; Kulkarni et al., 1987). Also, there are reports of deficiency signs in rats and mice fed highly purified diets in the absence of pyrroloquinoline quinone, a cofactor for oxidoreductases (Anonymous, 1988). Nutrition studies on such compounds will be watched with interest, but the data are far too few to establish even provisional requirements for humans.
Many other specific growth factors are known to be required in cell or tissue cultures and for bacteria, lower metazoa, or insects and other invertebrates. There is no evidence that such substances are required in the diets of humans or other higher animals, and since such substances can be synthesized in the tissues of higher animals, demonstration of need is highly unlikely. The substances in this category include asparagine, bifidus factor, biopterin, chelating agents, cholesterol, coenzyme Q (ubiquinones), hematin, lecithin, lipoic acid (thioctic acid), nerve-growth factors, p-aminobenzoic acid, various peptides and proteins, pimelic acid, and pteridines (Briggs and Calloway, 1984; Shils and Young, 1988).
SUBSTANCES WITH NO KNOWN ESSENTIALITY IN ANIMALS OR HUMANS
No essential nutrient function in animals or plants has ever been reported in reliable scientific literature for most other organic chem-
icals occurring naturally in foods or otherwise endogenously synthesized. Compounds in this category include amygdalin or laetrile (incorrectly referred to as vitamin B17) (Herbert, 1988), chlorophyll, orotic acid, pangamic acid (an ill-defined mixture of dimethylglycine and sorbitol that is incorrectly called vitamin B15), so-called vitamin U, and any other herbs, growth factors, enzymes, hormones, trace elements, or other compounds called vitamins or minerals not mentioned elsewhere in this report (Briggs and Calloway, 1984; Shils and Young, 1988).
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