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Page 311 11 Fat-Soluble Vitamins Small amounts of vitamins are required in the diet to promote growth, reproduction, and health. Vitamins A, D, E, and K are called the fat-soluble vitamins, because they are soluble in organic solvents and are absorbed and transported in a manner similar to that of fats. Dietary Sources, Patterns of Intake, and Levels of Fat-Soluble Vitamins Vitamin A: Carotenoids and Retinoids Vitamin A is required for the maintenance of normal mucous membranes and for normal vision. It occurs naturally only in foods of animal origin, such as liver, butter, whole milk, and egg yolks, but the body converts certain carotenoids, especially b-carotene, to vitamin A. Only 50 of the more than 500 naturally occurring carotenoids have provitamin A activity (Isler et al., 1971; Olson, 1983, 1984). Carotenoids are present in dark-green, leafy vegetables and in yellow and orange vegetables and fruits. In addition, skim milk, margarines, and certain breakfast cereals are fortified with vitamin A. From food composition tables, one can estimate only the total vitamin activity (vitamin A value) but not the quantity of specific carotenoids or retinoids in foods (Beecher and Khachik, 1984). However, researchers are now beginning to add carotenoid values to those in the U.S. Department of Agriculture (USDA) data bank. In 1980 the Recommended Dietary Allowance (RDA) for males 11 years of age and older was 1,000 retinol equivalents (RE), or 5,000 International Units (IU), and for females, 800 RE (4,000 IU) (NRC, 1980). By definition, 1 RE is equal to 1 µg of retinol, 6 µg of b-carotene, or 12 µg of other provitamin A carotenoids. One IU of vitamin A activity is defined as 0.3 µg of retinol and as 0.6 µg of b-carotene. One RE is equal to 3.33 IU of vitamin A activity from retinol and to 10 IU of vitamin A activity from b-carotene. Many food composition tables and most food labels still list vitamin A activity in IU, although the official unit is now RE. The availability of vitamin A in the food supply rose from 7,300 IU per capita in 1967-1969 to 9,900 IU in 1985, an increase of 37% (see Table 3-3). This increase was due chiefly to new varieties of carrots containing higher amounts of carotenoids. The 1977-1978 Nationwide Food Consumption Survey, based on 3-day dietary intake reports, indicated that total vitamin A intakes averaged 133% of the RDA. More than two-thirds of the population had intakes of at least 70% of the RDA. Intakes were higher for adults
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Page 312 over 64 years of age and for children under 8 than for other age groups. People above poverty levels were more apt to reach the RDA for vitamin A than were those below. Intakes were highest in the western United States and lowest in the South (DHHS-USDA, 1986). According to the 1976-1980 National Health and Nutrition Examination Survey (NHANES II), total mean dietary intake of vitamin A in the U.S. population, excluding infants, was approximately 1,000 RE. Carotenoids and preformed vitamin A contributed 25 and 75%, respectively, of the total intake. Mean serum vitamin A levels measured in NHANES II were within normal ranges for all race, sex, and economic groups. Vitamin D The active form of vitamin D promotes intestinal absorption of calcium and phosphorus and influences bone mineralization. Vitamin D occurs in two forms that are equally well utilized in the body. Vitamin D2 (ergocalciferol) is produced commercially by ultraviolet (UV) irradiation of the plant sterol ergosterol; vitamin D3 (cholecalciferol) is formed by the action of sunlight on the precursor 7-dehydrocholesterol in the skin. The human body utilizes both forms of vitamin D by hydroxylating first the 25-position in the liver and then the 1a-position in the kidney, producing the biologically active 1a,25-dihydroxycalciferols. Vitamin D occurs naturally only in animal foods such as liver, butter, fatty fish (fish containing high levels of cholesterol or fatty acids as glycerides), and egg yolks. Because natural milk is a poor source, it is fortified with vitamin D to provide 10 µg (400 IU) per quart. The amount of vitamin D formed by exposure of skin to sunlight depends upon the length of the UV irradiation, the intensity, which can be diminished by atmospheric pollution, and skin pigmentation. Aging skin may have diminished capacity to synthesize vitamin D (MacLaughlin and Holick, 1985). The 1980 RDAs for vitamin D are set at 10 µg (400 IU) of cholecalciferol per day during periods of growth (childhood, pregnancy, lactation) and 5 µg (200 IU) per day for nonpregnant, nonlactating adults. National surveys in the United States have never monitored vitamin D intake or nutritional status. Recent studies suggest that some elderly people may exhibit poor vitamin D status (Omdahl et al., 1982; Parfitt et al., 1982). Vitamin E Vitamin E is an important antioxidant that is thought to protect polyunsaturated fatty acids from oxidative destruction in cell membranes. Vitamin E activity in foods is due to the presence of tocopherols and tocotrienolscompounds of plant origin. The most important of these is a-tocopherol; less active are b-tocopherol, g-tocopherol, and a-tocotrienol. Vegetable oils are the richest source of vitamin E. Other good sources include nuts, seeds, whole grains, and wheat germ. The vitamin E content of animal foods is generally low. The RDA for adults is 8 mg of a-tocopherol equivalents (a-TE) or 12 IU for females age 11 and older and 10 mg of a-TE (15 IU) for males age 15 or older. The need for vitamin E is increased if the polyunsaturated fat intake is high, but in the U.S. food supply, foods with high levels of polyunsaturated fatty acids also have a high vitamin E content. Vitamin E was not included in national surveys until 1985, when the Continuing Survey of Food Intakes of Individuals was initiated by USDA. In 1985, this survey indicated that on the average, women 19 to 50 years of age consumed 97% of the RDA for vitamin E (USDA, 1987). Vitamin K Vitamin K is needed in the liver for formation of several blood clotting factors. Vitamin K1, (phylloquinone) is synthesized by plants, whereas vitamin K2 homologs (menoquinones) are synthesized by bacteria. The human body can obtain vitamin K from dietary sources as well as through synthesis by the gut microflora. Larger amounts of vitamin K are present in dark-green leafy vegetables; lower levels are found in cereals, dairy products, meats, and fruits. A committee of the Food and Nutrition Board estimated the safe and adequate intake range for adults to be 70 to 140 µg per day. The lower end of that range was based on the assumption that half the daily vitamin K intake is supplied by the diet and that half comes from intestinal synthesis. The higher end of the range represents intake derived entirely from diet. The usual diet of the U.S. population contains 300 to 500 µg per day, and there are no reports of vitamin K deficiency or toxicity in the general population; thus, it has been assumed that dietary intake of vitamin K does not need to be monitored (NRC, 1980).
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Page 313 Evidence Associating Fat-Soluble Vitamins with Chronic Diseases Vitamin A: b-Carotene and Other Carotenoids Cancer Human Studies of Lung Cancer Early epidemiologic studies focused generally on foods with vitamin A activity but did not distinguish between b-carotene and retinol (NRC, 1982). A 5-year prospective study of 8,278 Norwegian men indicated that intake of foods with vitamin A activity was inversely associated with incidence of lung cancer independently of cigarette smoking (Bjelke, 1975). This result was extended to women as well as men in the 11-year follow-up of Bjelke's study (Kvale et al., 1983) and in hospital-based case-comparison studies in the United States (Mettlin et al., 1979) and in the United Kingdom (Gregor et al., 1980). Peto et al. (1981) hypothesized that the relevant dietary exposure was b-carotene rather than retinol. This was subsequently supported by a 19-year prospective study of 1,954 middle-aged men in Chicago (Shekelle et al., 1981) and population-based case-comparison studies in New Jersey (Ziegler et al., 1984), Hawaii (Hinds et al., 1984), and New Mexico (Samet et al., 1985). Two other studiesa 10-year prospective study of 265,118 adults in Japan (Hirayama, 1979) and a hospital-based case-comparison study of Chinese in Singapore (MacLennan et al., 1977)indicated that lung cancer risk was inversely associated with the frequency of eating green and yellow vegetables. Retrospective studies of serum b-carotene levels and lung cancer risk are difficult to interpret, because the disease itself may affect the variable under study. In two prospective studies, blood samples were taken from subjects before they developed cancer. One was conducted in men of Japanese ancestry in Hawaii (Nomura et al., 1985) and another in white adults in Washington County, Maryland (Menkes et al., 1986). Blood samples were taken from people apparently free of cancer and stored at -70°C or lower (to prevent oxidative loss of b-carotene). Beta-carotene was subsequently measured by high-performance liquid chromatography (HPLC) in subjects who developed cancer and in controls. In both studies, b-carotene concentrations in serum were associated inversely with lung cancer risk independently of cigarette smoking. Clinical trials to determine the effect of dietary b-carotene supplements on lung cancer are in progress, but results are not yet available. Human Studies of Cancers Other Than Lung Cancer As with lung cancer, early studies of other cancers and food intake generally focused on vitamin A activity without making a distinction between b-carotene and retinol. Two case-comparison studiesone in Norway and Minnesota (Bjelke, 1974) and one in Pennsylvania (Stehr et al., 1985)indicated an inverse association between intake of foods with vitamin A activity and gastric cancer risk. In contrast, a series of case-comparison studies conducted at Roswell Park, reported by Graham and colleagues (1983) (Graham et al., 1960, 1963, 1967, 1978, 1983; Mettlin and Graham, 1979), showed no association between intake of foods with vitamin A activity and gastrointestinal cancer. However, they did find that intake of such foods was inversely associated with cancers of the bladder, mouth, larynx, esophagus, and breast and was positively associated with cancer of the prostate (Graham, 1983; Graham et al., 1983). In a hospital-based case-comparison study conducted in Italy, dietary intake of b-carotene, but not of retinol, was inversely associated with risk of invasive cervical cancer after adjustment for risk factors such as age at first intercourse, number of sexual partners, and educational status (La Vecchia et al., 1988). This result supports two earlier case-comparison studies in the United States (Marshall et al., 1983; Wylie-Rosett et al., 1984). A 5-year prospective study of 1,271 Massachusetts residents 66 years of age or older demonstrated an inverse association between frequency of eating green and yellow vegetables and risk of death from cancer after adjustment for age, smoking habits, sex, and total food intake (Colditz et al., 1985). A case-comparison study in Israel suggested a strong, graded inverse association between the number of carotene-containing foods eaten daily and risk of gastrointestinal cancer (Modan et al., 1981); however, no association was found with intake of dietary b-carotene itself. The investigators concluded that the association with foods was probably due to factors other than b-carotene. In three case-comparison studies, intake of foods with vitamin A activity was positively associated with risk of prostate cancer. Two groups of investigators (Graham et al., 1983; Heshmat et al., 1985) did not analyze their data separately for
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Page 314 carotenoids and retinoids. A third group (Kolonel et al., 1987) found a positive association with carotenoids and retinoids for men aged 70 or older but not for younger men. In a prospective study by Nomura et al. (1985), there was no statistically significant association between concentrations of serum b-carotene and 10-year risk of cancers of the colon, stomach, rectum, and urinary bladder, although, as noted above, an inverse association with lung cancer was observed. However, since the statistical test was not particularly powerful and the mean concentrations of serum b-carotene in cases of stomach and colon cancer (22.8 and 23.5 µg/dl, respectively) were lower than those in the comparison group (29.0 µg/dl), these data are consistent with a hypothesis of an inverse association as well as the hypothesis of no association. In another prospective study, Willett et al. (1984) found no association between serum total carotenoid concentration and 5-year risk of cancer. The implications of this evidence for hypotheses specifically about b-carotene are limited, because b-carotene comprises only about 20 to 25% of total carotenoids in serum (Katrangi et al., 1984), and the correlation between concentrations of b-carotene and total carotenoids in serum is only .6 to .7 (Russell-Briefel et al., 1985). Several clinical trials testing supplemental b-carotene as a chemopreventive agent are currently under way, but no results have yet been published. There has been one study, however, in which dietary supplementation with retinol and b-carotene was found to decrease markedly the proportion of micronucleated buccal mucosal cells in Filipino betel chewers (Stich et al., 1984). Animal Studies Only a few studies have explored the potential chemopreventive effects of carotenoids on experimentally induced tumors in animals. The incidence of tumors decreased and the latent period for development of tumors increased in mice fed supplemental b-carotene before inoculation with Moloney's sarcoma virus; the rate of tumor regression markedly increased when b-carotene was fed after tumors were already present (Seifter et al., 1982). Similar results were obtained in mice inoculated with C3HBA adenocarcinoma cells. Injection of b-carotene decreased the incidence of skin cancer in hairless mice exposed to ultraviolet-B (UV-B) radiation (Epstein, 1977a). Both b-carotene and canthaxanthin, a carotenoid without vitamin A activity, decreased the incidence of skin cancer in mice exposed to benzo[a]pyrene and UV light (Santamaria et al., 1983). b-Carotene, canthaxanthin, and phytoene, another carotenoid without vitamin A activity, decreased the incidence of skin tumors and increased the latent period in mice exposed to UV-B only, but only b-carotene exerted these effects in mice exposed to dimethylbenzanthracene (DMBA) (Mathews-Roth and Krinsky, 1984). In at least one study, growth of tumor cells was not suppressed in mice injected with b-carotene (Tomita, 1983). More information is clearly needed concerning the potential roles of specific carotenoids as chemopreventive agents for specific neoplasms in laboratory animals. In Vitro Assays: Possible Mechanisms of Action Peto et al. (1981) suggested several possible mechanisms through which dietary carotenoids might be able to affect cancer risk. These include (1) a direct or indirect retinoid-like effect (as described below) on cellular differentiation in target tissues (including possible conversion to retinoids in the target tissue), (2) their action as antioxidants, thereby protecting against transformation, and (3) protection afforded through some other mechanism (for example, by enhancing some immunologic function). See also Dimitrov (1986) and Willett and MacMahon (1984) for reviews and references. Bendich and Shapiro (1986) reported that T- and Blymphocyte responses were enhanced in rats fed b-carotene or canthaxanthin. b-Carotene is highly effective in quenching singlet oxygen and in trapping free radicals. These potent antioxidant effects of carotenoids may protect cells against oxidative damage to DNA, thereby exerting a chemopreventive effect against cancer (Dimitrov, 1986). Hypercarotenemia The intake of very large quantities of b-carotene can result in elevated plasma carotene levels (hypercarotenemia) and a yellow-orange pigmentation of the skin (carotenodermia). This condition is clinically innocuous and reversible. Furthermore, abnormally elevated plasma levels of vitamin A and clinical evidence of hypervitaminosis A do not result from the consumption of high doses of b-carotene. The medical induction of hypercarotenemia has been used successfully in the treatment of photosensitive conditions in humans (Mathews-Roth, 1982). Other Diseases Carotenoids in plants and long-chain retinyl esters in animal tissues are the major natural
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Page 315 sources of vitamin A, which is necessary for growth, health, vision, reproduction, and maintenance of differentiated epithelia and mucus secretion. Thus, to the extent that other sources of vitamin A are absent, a decreased intake of carotenoids with vitamin A activity, especially b -carotene, can be a cause of hypovitaminosis A. In her review of carotenoids in medical applications, Mathews-Roth (1982) noted that certain conditionsfor example, menstrual disorders and leukopeniahave been observed in persons who habitually consume very large quantities of carotenoid-containing foods. She concluded, however, that these were not effects of b -carotene specifically, because such abnormalities have not been observed in persons taking pure b -carotene. Vitamin A: Retinol and Other Retinoids Cancer Human Studies Among early studies not distinguishing between retinol and b-carotene, one case-comparison study found that vitamin A supplementation was associated with lower cancer risk (Smith and Jick, 1978), and another found that the inverse association between vitamin A intake and lung cancer risk was due primarily to intake of liver and vitamin A preparations (Gregor et al., 1980). However, the weight of evidence from several studies (e.g., La Vecchia et al., 1988; Samet et al., 1985; Shekelle et al., 1981; Ziegler et al., 1984) indicates that intake of preformed vitamin A, either by diet or by supplementation, is not associated with decreased risk of cancer. In fact, Modan et al. (1981) found that some retinol-containing foods were positively associated with risk of gastrointestinal cancers, but it seems more likely that the association was due to the lipid composition of these foodseggs, butter, sour creamthan to the vitamin A content. As mentioned earlier, three case-comparison studies (Graham et al., 1983; Heshmat et al., 1985; Kolonel et al., 1987) indicated a positive association between intake of foods with vitamin A activity and risk of prostate cancer. It is not possible, however, to separate clearly the potential effects of dietary carotenoids, retinoids, and other food components in this association. Prospective studies in London (Wald et al., 1980), Evans County, Georgia (Kark et al., 1981), and eastern Finland (Salonen et al., 1985) were reported to show that there is an inverse association between serum levels of retinol and subsequent risk of cancer, particularly in the lung. However, a second study of the Evans County population by Peleg et al. (1984) failed to confirm the first study's results. Two large studies, by Friedman et al. (1986) and by Menkes et al. (1986), provide strong evidence that serum retinol concentrations are not associated with risk of lung cancer. Other studies (Nomura et al., 1985; Stähelin et al., 1984; Willet et al., 1984) indicate that serum retinol concentration is not associated with cancer risk generally. It now seems unlikely that variation in retinol intake or in serum retinol concentrations within the normal range is associated with cancer risk generally or lung cancer risk specifically. Nonetheless, it still is possible that deficiency in vitamin A nutriture may affect the incidence of cancer in populations. Yang et al. (1984) found low average plasma levels of retinol, b-carotene, and a-tocopherol in Linxian, a province in northern China with very high incidence rates of esophageal cancer. Systematic studies of the ecological correlation between vitamin A nutriture and cancer risk have not yet been reported. Animal Studies Wolbach and Howe (1925) reported that vitamin A deficiency resulted in a change in cell differentiation and in keratinization of epithelia in the respiratory tract, salivary glands, eyes, and genitourinary tract. Much subsequent work (described below) shows that retinoids profoundly affect the differentiation and proliferation of cells. The activity of retinoids in preventing, suppressing, or retarding experimentally induced cancer in animals has been studied extensively in a variety of animal models; see Moon and Itri (1984) and Sporn and Newton (1981) for reviews and references. Retinoids are highly effective in the prevention of experimental cancer of the skin, breast, and bladder (see, e.g., Bollag, 1975; Davies, 1967; Epstein and Grenkin, 1981; McCormick et al., 1980; Moon et al., 1977; Saffiotti et al., 1967; Schmähl and Habs, 1978; Shklar et al., 1980; Sporn and Newton, 1979). Promising but less definitive results have been obtained in studies of the prevention of carcinogenesis at a number of other sites, including the pancreas, prostate, lung, esophagus, and colon. Not all studies have shown that retinoids decrease susceptibility to experimentally induced cancer, and some studies have re-
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Page 316 ported no effect or even increased susceptibility (Epstein, 1977b; Levij and Polliack, 1968; Nettesheim, 1980; Smith et al., 1975a,b; Ward et al., 1978; Welsch et al., 1981). Wholly satisfactory explanations for these variations are not yet available. Overall, however, the strong preponderance of evidence from experimental animal studies shows that vitamin A deficiency enhances chemically induced carcinogenesis in many animal tissues and that retinoids can exert a protective or preventive effect against many kinds of cancer (NRC, 1982). In Vitro Assays: Possible Mechanisms of Action Retinoids have powerful effects on cell differentiation and proliferation (for reviews and references, see Goodman, 1984; Roberts and Sporn, 1984; Sporn and Roberts, 1983, 1984). They have been used extensively in studies in vitro to induce cell differentiation in organ and cell culture systems, especially in the hamster tracheal organ culture system (Sporn and Newton, 1981). Retinoids affect the differentiation of neoplastic and nonneoplastic cells in culture and can act directly on nonneoplastic cells to suppress malignant transformation induced by chemical carcinogens, radiation, or transforming growth factors. Furthermore, they can induce terminal differentiation of neoplastic cells, such as mouse embryonal carcinoma cells (Strickland and Mahdavi, 1978) and human promyelocytic leukemia cells (Breitman et al., 1980). Retinoids also counteract the effects of phorbol esters in a variety of systems. The molecular mechanisms through which retinoids exert these effects are not known. They may relate to signal transduction. It is likely that retinoids affect gene expression in target cells (Roberts and Sporn, 1984). Other Diseases Vitamin A deficiency is found frequently among young children in many poor and undernourished populations. Xerophthalmia is the most important clinical effect. Sommer (1982) estimated that approximately 500,000 new cases occur annually in India, Bangladesh, Indonesia, and the Philippines and that half these cases are likely to result in blindness. In the United States, nutrition surveys indicate that frank vitamin A deficiency does not occur frequently; however, borderline serum concentrations of vitamin A and reduced liver stores of vitamin A have been observed at autopsy (Goodman, 1984; Underwood, 1984). Excess intakes of retinol (hypervitaminosis A) can also have harmful effects on humans and other animals. This topic is discussed in Chapter 18. Vitamin D Vitamin D serves to maintain serum calcium concentrations, which in turn influence bone mineralization. Vitamin D as 1,25-dihydroxycholecalciferol [1,25(OH)2D] acts primarily to maintain the cellular calcium transport system in the intestine. Parathyroid hormone (PTH) and vitamin D are interdependent: the renal production of 1,25(OH)2D depends on the prevailing concentration of PTH in the blood, and the ability of PTH to increase plasma calcium depends on a calcium transport system maintained by 1,25(OH)2D. Vitamin D stimulates an active calcium transport system that increases calcium absorption in the small intestine (DeLuca, 1988; DeLuca et al., 1982; Nicolaysen and Eeg-Larsen, 1953; Wasserman and Feher, 1977). It also acts in bone mineralization primarily by maintaining adequate plasma concentrations of calcium and phosphorus, rather than by having a direct trophic effect on bone (Holtrop et al., 1981; Underwood and DeLuca, 1984; Weinstein et al., 1984). Vitamin D also plays an important role in bone remodeling. The exact mechanism by which vitamin D maintains normal bone development is unknown, but disorders of the vitamin D endocrine system are the leading cause of osteomalacia through decreased bioavailability of vitamin D, abnormal metabolism, and abnormal response of target tissues to the biologically active vitamin D metabolites (Bikle, 1985). Osteoporosis and Osteomalacia Human Studies The term osteoporosis refers to a group of disorders with various etiologies that is characterized by a decrease in bone mass per unit volume. In cases of osteoporosis, bone has a normal ratio of mineral to matrix. Osteomalacia refers to a disorder in which there is abnormal bone mineralization and the ratio of mineral to matrix is diminished due to an excess of unmineralized osteoid. Two patterns of osteoporosis have been postulated: postmenopausal and senile. Postmenopausal osteoporosis affects predominantly trabecular bone in women and is manifested as vertebral fractures that occur particularly during the 15 to 20 years after menopause. Senile osteoporosis affects corti-
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Page 317 cal and trabecular bone in women and men and results in vertebral and hip fractures after age 75 (Riggs et al., 1982). In countries with limited sunlight or where the population dresses in a fashion that minimizes sunlight exposure, circulating levels of vitamin D metabolites are often low. This might explain why there is a higher incidence of osteomalacia in Great Britain, Scandinavia, the Middle East, India, and other Muslim countries than in the United States (Bikle, 1985). In the United States, nutritional deficiency of vitamin D is uncommon; however, it may occur in children of vegetarians who avoid milk products (and likely have low stores of vitamin D) and in children who are not weaned to vitamin D-supplemented milk by age 2. The contribution of nutritional vitamin D deficiency to osteomalacia in the elderly is unknown. One of the many causes of osteoporosis is decreased calcium absorption. There is a dispute whether this decreased absorption can be correlated with decreased circulating levels of 1,25(OH)2D (Crilly et al., 1981; Gallagher et al., 1979; Nordin et al., 1979). Nevertheless, calcium absorption markedly improves by administering small doses of 1,25(OH)2D (Finkelman and Butler, 1985). Riggs et al. (1979) found that treatment of postmenopausal osteoporotic females with as little as 0.5 µg per day greatly improved calcium balance. Caniggia et al. (1986) noted a dramatic improvement in the intestinal transport of calcium in subjects treated with 1,25(OH)2D, but the increases in bone mineral content were not significant. These results are in agreement with those of Gallagher et al. (1982), who reported that treatment with 1,25(OH)2D improved net calcium absorption and balance and increased trabecular bone volume in a controlled study in postmenopausal osteoporotic women with one or more traumatic vertebral fractures. Investigators in Finland reported that serum 25-hydroxycholecalciferol (25-OH-D) concentrations were lower in patients with hip fractures than in age-matched controls (Harju et al., 1985). They attribute this to lack of sunlight exposure and insufficient dietary vitamin D intake. Those authors suggest that elderly disabled persons should be given vitamin D supplements. Caniggia et al. (1986) reported that serum bone g-carboxyglutamyl-protein levels increased in postmenopausal osteoporotic women treated with 1,25(OH)2D. They attributed this to osteoblast stimulation, suggesting that the osteoblasts do not lose their sensitivity to this stimulus during postmenopausal osteoporosis. The implications of this are uncertain. Animal Studies Adult rats were fed a calcium-deficient diet for 6 weeks and subsequently fed a combination of 1a-hydroxycholecalciferol (1a-OH-D3) and optimal levels of calcium (Lindholm et al., 1981) for 6 weeks. Osteoporosis as well as morphological changes of the parathyroids were almost totally reversed. In another study, when calcium-deficient mice were refed calcium alone, reversal of osteoporotic changes was not complete (Sevastikoglou et al., 1977). In the rat liver, 1a-OH-D3 is converted to 1,25(OH)2D3. It is known to promote calcium absorption in the small intestine and to increase resorption of calcium in the kidneys. It may also act through direct or indirect mechanisms on bone tissue to promote new bone formation (Kraft et al., 1979; Kream et al., 1977; Lindholm et al., 1981). Mechanisms of Action and Interactions Interaction of vitamin D with other nutrients, particularly calcium, was addressed in the preceding sections; thus, only a brief overview is presented here. The vitamin D endocrine system is an important regulator of calcium homeostasis. The metabolite that plays the most important physiological role in calcium and bone metabolism is 1,25(OH)2D (both D2 and D3 forms), which is also referred to as the hormonal form of vitamin D. This extremely active form does not vary with the amount of vitamin D synthesis or ingestion, and its concentration remains relatively constant over a broad range of 25-OH-D serum concentrations. 1,25(OH)2D is important in the control of calcium absorption through the small intestine and is involved in both bone calcification and bone resorption. Resorption of bone appears to be tightly coupled to the formation of new bone in vivo and in vitro. A decrease in serum 1,25(OH)2D has been noted in patients with osteoporosis (Goldsmith, 1984); however, it is unclear if vitamin D deficiency is an important risk factor for bone loss in most aging American women (Tsai et al., 1987). The entire sequence proposed is: estrogen deficiency ® increased calcium release from bone ® decreased PTH secretion ® decreased conversion of 25-OH-D to 1,25(OH)2D ® decreased calcium absorption. Thus, estrogen deficiency may be the primary cause or the trigger of the subsequent events
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Page 318 resulting in decreased calcium absorption. Hence, 1,25(OH)2D plays an important role in maintaining normal calcium homeostasis by increasing the intestinal absorption of calcium. Aging Low serum calcium levels predispose to osteoporosis. A low calcium intake is a particular hazard in the elderly because they cannot adapt by increasing calcium absorption. This may be due partly to their failure to produce a sufficient amount of 1,25(OH)2D in response to calcium deficiency, perhaps because of an impaired response of renal 1a-hydroxylase to PTH (Raisz and Johannesson, 1984). Increased supplementation with 25-OH-D as a substrate may not result in increased synthesis of 1,25(OH)2D in elderly women. Lukert et al. (1987) observed a negative correlation between serum 25-OH-D and PTH hormone levels in perimenopausal women and elderly men, but not in elderly, postmenopausal women. They also observed a significant negative correlation between bone loss and serum 25-OH-D in elderly postmenopausal women. Whether or not the serum level of 1,25(OH)2D is decreased in elderly osteoporotic women is uncertain. Gallagher et al. (1982) reported a causal relationship between the osteoporotic state and decreased serum 1,25(OH)2D levels as well as calcium absorption rates. In contrast, Christiansen and Rødbro (1984) reported that serum 1,25(OH)2D concentrations were virtually the same in 44 early postmenopausal women and 28 women 70 years of age with and without osteoporotic fractures. Tsai et al. (1984) suggest that elderly women have abnormal vitamin D metabolism. In their study of pre- and postmenopausal normal and osteoporotic women, they noted that the kidneys of elderly subjects had a decreased ability to synthesize 1,25(OH)2D. They concluded that this may contribute to the pathogenesis of senile osteoporosis. These results were confirmed in another study by Tsai et al. (1987), in which they measured serum levels of 25-OH-D2, 25-OH-D3, and total 25-OH-D and used single and dual photon absorptiometry to measure bone mineral density. They found no association between any of the vitamin D metabolites and any of three skeletal scanning sites; however, they noted that levels of serum total 25-OH-D and serum 25-OH-D3 decrease with age, which may be related to several factors. The elderly are often malnourished and are less likely to be exposed to the sun (Parfitt et al., 1982). In addition, there are decreases in vitamin D absorption (Barragry et al., 1978) and dermal biosynthesis after exposure to sunlight (Holick and MacLaughlin, 1981). Renal Disease Metabolic studies indicate that vitamin D acts in the kidney with PTH to stimulate the final resorption of calcium in the distal tubule (DeLuca, 1979; Sutton et al., 1977). This probably leads to the resorption of an additional 1%7 to 10 g of calcium (DeLuca, 1981). In renal disease, these normal events and the 1a-hydroxylation of 25-OH-D can be impaired. Vitamin E Cancer Human Studies The prospective epidemiologic studies reviewed below suggest that vitamin E intake is in itself not related to overall risk of cancer, but that low serum levels of vitamin E coupled with low serum levels of selenium may increase the risk of at least some cancers. Additional studies are needed to investigate this hypothesis and to determine whether intake of vitamin E may be related to risk of specific cancers, for example, of the breast and lung. At entry into the Hypertension Detection and Follow-up Program in 1973-1974, venous blood specimens were collected from 10,940 participants at least 4 hours after their last meal and sera were stored at -70°C (Willett et al., 1984). The investigators subsequently measured retinol, a-tocopherol, and total carotenoids in the serum of 321 participants who were apparently free of cancer at entry. Five years later, 111 of these participants were diagnosed as having cancer [17, lung; 14, breast; 11, prostate; 11, leukemia or lymphoma; 11, gastrointestinal (GI) tract, and 40, other sites excluding nonmelanoma skin cancers]. The other 210 subjects (matched with cases for age, sex, race, smoking history, and other characteristics) did not have a diagnosis of cancer during 5 years of follow-up from the start of the study. The two groups did not differ significantly in mean concentration of serum a-tocopherol; the unadjusted mean values for cases and controls were 1.16 and 1.26 mg/dl [crude difference = -0.10, standard error (SE) = 0.06, p = .23]. After adjustment for total lipids, the difference was -0.05 (SE = 0.06, p = .68). Similar results were obtained when the data were analyzed according to site. These results do not support the hypothesis that low serum
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Page 319 vitamin E by itself is associated with overall incidence of cancer. In an earlier paper from this same study, however, Willett et al. (1983) reported that the cancer risk associated with low serum selenium appeared strongest in persons with low serum vitamin E. Wald et al. (1984) studied 5,004 women aged 28 to 75 in Guernsey, United Kingdom, who gave blood between 1968 and 1975. The plasma was stored at -20°C. By the end of 1982, general practitioners reported 39 cases of breast cancer in women whose plasma samples were available for analysis. The stored samples for these women and samples from 78 controls were matched 2-to-1 for menopausal status, parity, family history of breast cancer, and history of benign breast disease. Vitamin E was significantly lower in cases (0.47 mg/dl) than in controls (0.60 mg/dl)p < .025after adjusting for age of subject and duration of plasma storage. The adjusted relative odds of breast cancer according to plasma levels of vitamin E were only meaningful below 0.5 mg/dl. In Basel, Switzerland, between 1971 and 1973, Stähelin et al. (1984) measured vitamin E in fresh samples of fasting blood from employed men who volunteered for venipuncture. It is unclear whether or not they excluded subjects with evidence of cancer. They conducted a mortality follow-up of this cohort through 1980. Information regarding cancer in subjects who died during this 7- to 9-year period was obtained from death certificates, autopsies, and a cancer registry. Mean concentrations of plasma vitamin E for men who died with a diagnosis of cancernotably of lung, stomach, and colondid not differ significantly from those for age-matched men who were still alive in 1980. In 1977, Salonen et al. (1985) collected (and stored at - 20°C) sera from a random 6.7% sample of 30- to 64-year-old people living in two provinces of eastern Finland. Deaths were ascertained through 1980, and diagnoses of cancer on the death certificate were confirmed from hospital records. Serum concentrations of a-tocopherol, selenium, and retinol were measured for 51 persons who died of cancer (18, GI tract; 15, lung; and 18, other sites) and 51 controls matched for sex, age, and number of tobacco products smoked daily. Cases did not differ significantly from controls in either mean concentration of serum a-tocopherol (4.9 and 5.0 mg/dl, respectively) or mean ratio of a-tocopherol to cholesterol (18.9 and 20.8%, respectively). However, multivariate analysis showed a strong interaction between selenium and a-tocopherol. After adjustment for main effects, the relative risk of fatal cancer for persons in the lower tertile of selenium and of a-tocopherol levels was 11.4. From 1971 through 1975, as part of the Honolulu Heart Program, nonfasting serum specimens were obtained (and stored at -75°C) from 6,860 men of Japanese ancestry who were born between 1900 and 1919 and lived on Oahu (Nomura et al., 1985). Subsequent cancer diagnoses were monitored by continuous surveillance of all general hospitals on Oahu and through the Hawaii Tumor Registry. After 10 years of follow-up, 284 newly diagnosed cases of epithelial cancer, all confirmed histologically, were identified: 81, colon; 74, lung; 70, stomach; 32, rectum; and 27, urinary bladder. Controls (302) were randomly selected from the examined men who did not have any of the cancers that were under study. This sampling was stratified by age group so that the age distribution of all cases combined could be matched. The mean serum concentrations of vitamin E in controls and in men with cancer of the lung, stomach, colon, rectum, and bladder were 12.3, 12.8, 12.2, 12.2, 11.6, and 12.7 mg/dl, respectively; none of the case-control differences was statistically significant. Menkés and Comstock (1984) noted that serum vitamin E levels were significantly lower (p = .01) in 88 persons who subsequently developed lung cancer than in 76 controls matched for age, sex, date of venipuncture, and smoking history. Animal Studies Jaffe (1946) reported that wheat germ oil inhibited production of methylcholanthrene-induced tumors in rats. Subsequently, several investigators conducted studies to determine if vitamin E was effective in preventing sarcomas and cancers of the mouth, skin, and breast in animals, but their results have been mixed. Haber and Wissler (1962) observed some inhibition of sarcoma formation in mice injected with 3-methylcholanthrene, but such inhibition was not found by Epstein et al. (1967), who exposed mice to 3,4,9,10-dibenzpyrene. Constantinides and Harkey (1985) reported that a-tocopherol, administered subcutaneously in a base of soya oil, produced vigorously growing sarcomas at the site of injection in 77% of animals, but they did not determine whether the effect was due to the soya oil, the vitamin E, or the combination. Shklar (1982) noted that twice-weekly vitamin E supplementation of the diets of hamsters exposed to dimethylbenz[a]anthracene resulted in fewer,
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Page 320 smaller, and less invasive oral tumors than in hamsters whose diets were not supplemented with vitamin E. Odukoya et al. (1984) observed fewer and smaller oral tumors in hamsters after topical application of vitamin E than in hamsters to which vitamin E was not topically applied. Shamberger (1970) found that a-tocopherol reduced the incidence of skin cancer in mice when administered with a promoting agent (croton oil) but not when given simultaneously with 7,12-dimethylbenz[a] anthracene. Slaga and Bracken (1977) noted only minimal effect of vitamin E when measuring epidermal metabolic activity. Pauling et al. (1982) observed no effect of vitamin E supplementation on incidence of squamous cell carcinomas in hairless mice exposed to UV radiation. These results indicate that the role of vitamin E in cancer inhibition is inconclusive at this time. Mechanisms of Action Vitamin E is an antioxidant and free-radical scavangerfunctions that may be responsible for an antineoplastic effect. Fiddler et al. (1978) and Mergens et al. (1978) reported that vitamin E, by competing for nitrates, blocks formation of nitrosamines and nitrosamides. Vitamin E may also regulate functions of coenzyme Q and of specific enzymes and proteins required for tissue differentiation. The stimulation of immune functions by vitamin E has also been suggested as an anticancer mechanism (Carpenter, 1986; Watson, 1986). Much of this work is speculative, however; anticancer mechanisms for vitamin E have not been definitively demonstrated. Atherosclerotic Heart Disease Vogelsang and Shute (1946) reported that large doses of vitamin E had a dramatic effect in the treatment of angina pectoris in an uncontrolled case-series study. That observation was not confirmed, however, in four placebo-controlled clinical trials (Anderson and Reid, 1974; Donegan et al., 1949; Makinson et al., 1948; Rinzler et al., 1950) and two double-blind trials (Anderson and Reid, 1974; Rinzler et al., 1950). Large doses of vitamin E were also tried in the treatment of intermittent claudication with mixed results (Farrell, 1980), but definitive studies of this question have never been done. Preliminary reports that vitamin E might raise the concentration of high-density lipoprotein cholesterol (Barboriak et al., 1982; Hermann et al., 1979) were not confirmed in a randomized, double-blind, placebo-controlled study by Stampfer et al. (1983). Others, however, reported that large vitamin E supplements might be associated with modest elevations in plasma triglycerides (Farrell and Bieri, 1975; Tsai et al., 1978). In another study, vitamin E did not appreciably affect the extent or severity of atherosclerosis in cynomolgus and cebus monkeys (Hayes, 1974). Other Diseases As an antioxidant, vitamin E may protect against free radicals implicated in cell damage leading to normal aging and to the development of neoplasia, but there are few reports of vitamin E deficiency in humans, except in the premature baby (Hassan et al., 1966; Oski and Barness, 1967). The incidence of retrolental fibroplasia in infants and very young children is decreased by vitamin E supplementation (Johnson et al., 1974). In older children and adults, severe vitamin E deficiency sometimes complicated by deficits of other vitaminsfor example folatehave led to muscular function alterations along with creatinuria, encephalomalacia, and hemolytic anemia (Binder et al., 1965). The reduced biliary excretion resulting from chronic intrahepatic obstructive jaundice (primary biliary cirrhosis) leads to steatorrhea and an associated decrease in absorption of fat-soluble vitamins, including vitamin E (Atkinson et al., 1956). Inadequate vitamin E absorption can be caused not only by intrahepatic cholestasis and extrahepatic biliary atresia but also by extensive therapeutic administration of bile acid-binding agents and the absence of water-soluble vitamin E preparations during therapy. Vitamin E can prevent progressive loss of neurological function in infants and children with prolonged neonatal cholestatic disorders (Guggenheim et al., 1983; Sokol et al., 1985). Morphological and functional alterations in the neuromuscular system result from the loss of antioxidant protection against free-radical-induced peroxidation of unsaturated fatty acyl moieties of membrane phospholipids (Muller et al., 1983; Neville et al., 1983). Slater and Swaiman (1977) suggested that increases in vitamin E intake may also prevent the deposition of ceroid in smooth muscle and pathological changes in the spinal cord unique to patients with cystic fibrosis. The efficacy of vitamin E in treating certain hematological and malabsorption disorders is no longer in doubt (Bieri et al., 1983). The evidence does not, however, support claims that increased supplements are beneficial for less experimentally documented purposes, for example, the delay of
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Page 321 carcinogenesis or cardiovascular diseases and the restoration of male potency (Horwitt, 1986). In premature infants, daily intravenous administration of 50 mg of all-rac-dl-tocopheryl acetate with emulsifiers was found to be toxic (Phelps, 1984). Also, megadoses of vitamin E inhibit vitamin K and can create complications in patients being treated with anticoagulants (Farrell and Bieri, 1975). Vitamin K Cancer Human Studies Chlebowski et al. (1984) conducted extensive research on vitamin K3 (menadione) and its effect on human and animal cell lines. In their study of a variety of human tumor lines, including explants from breast, colon, kidney, ovary, and lung, the vitamin resulted in decreased tumor colony-forming units. In a comparison of vitamins K1 and K3, vitamin K3 was found to be cytotoxic at much lower doses than the vitamin K1 preparation. Animal Studies Chlebowski et al. (1983) studied the effects of warfarin (a vitamin K antagonist) or vitamin K in conjunction with two standard chemotherapeutic agents, 5-fluorouracil (5-FU) and methotrexate, in L1210 cells. Both the warfarin and the vitamin K inhibited the salvage pathways used by the L1210 cells. These investigators suggest that the cytotoxicity of 5-FU and methotrexate could be enhanced with the addition of either vitamin K or warfarin. Israels et al. (1983) studied the effect of vitamins K1 and K3 on ICR/Ha mice. Mice receiving vitamin K3 developed tumors at a slower rate than did control mice or mice receiving vitamin K1. Indeed, in some animals, vitamin K1 was associated with accelerated benzo[a]pyrene tumorigenesis. These researchers indicated that vitamins K1 and K3 act at different metabolic sites as evidenced by benzo[a]pyrene activation and detoxification. Liver Disease Human Studies Severe parenchymal liver disease of several different etiologies can produce deficiencies in plasma clotting factors. This may be due to abnormal synthesis, increased utilization, or decreased production of clotting factors. Multiple factors can have a direct effect on hemostasis (Rock, 1984). For example, the vitamin K-dependent clotting factors II, VII, IX, and X and protein C require vitamin K for the carboxylation of the g-methylene group of glutamic acid residues. These residues are often located near the amino terminus of the peptide. In patients with parenchymal liver disease, the vitamin K-dependent carboxylase reaction may be impaired (Atkinson et al., 1979; Blanchard et al., 1981; Malia et al., 1980). Corrigan et al. (1982) reported that since protein synthesis is also altered in liver disease, reduced levels of inactive precursor and functional prothrombin are present, irrespective of activity of the carboxylase system. They also observed reduced levels of prothrombin antigen in patients with substantial liver disease. The more severe the hepatocellular damage, the more severe the reduction in the antigen level. The authors suggest that monitoring the level of factor II antigen seems to offer a more sensitive method than the standard prothrombin time for early detection of recovery from severe hepatic necrosis and dysfunction. Spontaneous hemorrhage or death has been associated with reduced factor II activity when it is less than 20% of normal (Deutsch, 1965; Tucker et al., 1973). When levels of the antigen are increased out of proportion to the clotting activity (normally coagulant activity closely approximates antigen, so the ratio of coagulant activity to antigen approaches unity), a secondary vitamin K deficiency is likely (Corrigan et al., 1982). Parenchymal liver disease results in hypoprothrombinemia, because the utilization of vitamin K in the biosynthesis of vitamin K-dependent clotting factors is impaired. This usually results from destruction of the rough endoplasmic reticulum in the hepatocyte (Suttie and Olson, 1984). Diminished synthesis of bile salts by the diseased liver results in steatorrhea and reduced ability to emulsify and absorb fat-soluble vitamins, including vitamin K. The clinical manifestations of the blood clotting disorder associated with vitamin K deficiency include ecchymoses, hematoma, and hemorrhage (Mezey, 1983). Malabsorption In addition to malabsorption resulting from liver cirrhosis and biliary diseases, other gastrointestinal disorders (e.g., cystic fibrosis, sprue, celiac disease, ulcerative colitis, regional ileitis, ascaris infection, short-bowel syndrome) can lead to depression of vitamin K-dependent coagulation factors (Suttie and Olson, 1984). Since as much as half the
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Page 322 vitamin K found in the adult liver is of the menaquinone (K2) type (Reitz et al., 1970), which is synthesized by intestinal microflora, a decrease in intestinal production, especially if dietary intake of phylloquinones (K1) is marginal can lead to problems. In early infancy, when intestinal synthesis is minimal (NRC, 1980), subjects are especially prone to vitamin K deficiency, which is exacerbated by antibiotic therapy for infantile diarrhea. Sulfa drugs, neomycin, and other broad-spectrum antibiotics can markedly decrease gut microflora and induce a hemorrhagic syndrome characteristic of vitamin K deficiency (Suttie and Olson, 1984). For example, apoplectic patients given neomycin and maintained on intravenous fluids deficient in vitamin K had lower than normal levels of clotting factors after 1 month (Frick et al., 1967). Other drugs that affect vitamin K status include those such as coumarin, which suppresses synthesis of g-carboxyglutamyl residues in vitamin K-dependent coagulation factors, or those that act indirectly by altering the effectiveness of such anticoagulants. The latter includes oxyphenbutazone, which enhances the effect of warfarin by displacing it from the albumin binding site, and barbiturates, which decrease the effect of warfarin by inducing hepatic inactivation (Young and Solomons, 1983). As pointed out above, high levels of vitamin E can also adversely affect vitamin K functions. This has been documented in laboratory animalsfor example, chicks (March et al., 1973)and in humans (Korsan-Bengsten et al., 1974). Vitamin K deficiency in patients taking megadoses of vitamin E (800 IU/day) has resulted in a hypersensitivity to the coumarin anticoagulants administered to patients (Corrigan and Marcus, 1974). Summary The intake of carotenoid-rich foods is inversely associated with risk of lung cancers of the types associated with cigarette smoking. Persons who smoke cigarettes and rarely or never eat carotenoid-rich foods have an appreciably greater risk of lung cancer than do comparable cigarette smokers who usually eat one or more servings of such foods daily. However, the consumption of carotenoid-rich foods does not necessarily serve as a protective factor against lung cancer for persons who smoke. The magnitude of the relative risk of both of these factors has not yet been well characterized. Studies also suggest an inverse association between b-carotene in serum and risk of lung cancer, but the evidence does not yet permit a conclusion that the association is with b-carotene specifically rather than some other carotenoid. In addition, intake of carotenoid-rich foods may be associated with a decreased risk of carcinomas at other sitesfor example, the uterine cervixbut the data are inconclusive. Neither intake of foods rich in preformed vitamin A nor serum concentrations of retinol appear to be associated with risk of cancer in humans, including cancer of the lung. However, the ability of retinoids to prevent, suppress, or retard some chemically induced cancers at sites such as the pancreas, prostate, lung, esophagus, and colon in animal models is well established. Evidence regarding anticancer roles for other fat-soluble vitamins is not persuasive. Intake of vitamin E by itself has not been related to overall risk of cancer, but the combination of low serum levels of vitamin E and selenium may be related to increased risk of some cancers, such as breast and lung cancers. Results of animal studies have been inconsistent, and anticancer mechanisms for vitamin E have not been established. Vitamin D influences bone mineralization by enhancing absorption of calcium from the intestinal tract and maintaining serum calcium concentrations. However, the exact mechanism by which this occurs is unknown. There is a higher incidence of osteomalacia among populations that avoid exposure to sunlight and such people often have low serum levels of vitamin D metabolites. The contribution of vitamin D deficiency to osteomalacia in the elderly is not known. Vitamin K2 is synthesized by intestinal microflora. A decrease in this synthesis, especially if dietary intake of vitamin K is low, can lead, for example, to vitamin K deficiency in infants. Vitamins K1 and K3 act at different metabolic sites and consequently their roles in the causation or prevention of cancer are not the same. Vitamin K status is affected by certain drugs such as sulfa drugs and other broad spectrum antibiotics. High levels of vitamin E can interfere with the clotting activity of vitamin K. Directions for Research · More information is needed concerning the potential roles of specific carotenoids as putative chemopreventive agents for specific neoplasms in laboratory animals. · Further studies, including clinical trials, should be conducted to examine the use of b-carotene in the prevention of cancers of the lung,
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Page 323 GI tract, and cervix. There is also a need for more observational studies on cancers of the GI and genitourinary systems. · Much of the data on vitamin E are correlational, and anticancer mechanisms for vitamin E have not been definitively demonstrated. Therefore, animal studies are needed to elucidate the association between vitamin E and cancer. · Research is needed to determine whether vitamin E deficiency in intact animals increases the risk of certain cancers, such as mammary tumors in mice, when combined with a high intake of polyunsaturated fat, and to define the optimal concentration of vitamin E in persons who increase their consumption of polyunsaturated fat. · The relationship between selenium and a-tocopherol and their possible role in altering cancer risk in humans should be elucidated. References Anderson, T.W., and D.B. Reid. 1974. A double-blind trial of vitamin E in angina pectoris. Am. J. Clin. Nutr. 27:1174-1178. Atkinson, M., B.E.C. Nordin, and S. Sherlock. 1956. Malabsorption and bone disease in prolonged obstructive jaundice. Q. J. Med. 25:299-312. Atkinson, P.M., M.C. Kew, A. Sayed, and B.A. Bradlow. 1979. The use of Dispholidus typus venom in elucidating the cause of a low prothrombin index. Clin. Lab. Haematol. 1:281-290. Barboriak, J.J., A.Z. Ghatit, K.R. Shetty, and J.H. Kalbfleisch. 1982. Vitamin E supplements and plasma high-density lipoprotein cholesterol. Am. J. Clin. Pathol. 77:371-372. Barragry, J.M., M.W. France, D. Corless, S.P. Gupta, S. Switala, B.J. Boucher, and R.D. Cohen. 1978. Intestinal cholecalciferol absorption in the elderly and in younger adults. Clin. Sci. Mol. Med. 55:213-220. Beecher, G.R., and F. Khachik. 1984. Evaluation of vitamin A and carotenoid data in food composition tables. J. Natl. Cancer Inst. 73:1397-1404. Bendich A., and S.S. Shapiro. 1986. Effect of beta-carotene and canthaxanthin on the immune responses of the rat. J. Nutr. 116:2254-2262. Bieri, J.G., L. Corash, and V.S. Hubbard. 1983. Medical uses of vitamin E. N. Engl. J. Med. 308:1063-1071. Bikle, D.D. 1985. Osteomalacia and rickets. Pp. 1425-1431 in J.B. Wyngaarden and LH. Smith, Jr., eds. Cecil Textbook of Medicine, Vol. 2. Saunders, Philadelphia. Binder, H.J., D.C. Herring, V. Hurst, S.C. Finch, and H.M. Spiro. 1965. Tocopherol deficiency in man. N. Engl. J. Med. 273:1289-1297. Bjelke, E. 1974. Epidemiologic studies of cancer of the stomach, colon, and rectum; with special emphasis on the role of diet. Scand. J. Gastroenterol. 9:1-235. Bjelke, E. 1975. Dietary vitamin A and human lung cancer. Int. J. Cancer 15:561-565. Blanchard, R.A., B.C. Furie, M. Jorgensen, S.F. Kruger, and B. Furie. 1981. Acquired vitamin K-dependent carboxylation deficiency in liver disease. N. Engl. J. Med. 305:242-248. Bollag, W. 1975. Prophylaxis of chemically induced epithelial tumors with an aromatic retinoid acid analog (RO 10-9359). Eur. J. Cancer 11:721-724. Breitman, T.R., S.E. Selonick, and S.J. Collins. 1980. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc. Natl. Acad. Sci. U.S.A. 77:2936-2940. Caniggia, A., R. Nuti, M. Galli, F. Loré, V. Turchetti, and G.A. Righi. 1986. Effect of a long-term treatment with 1,25-dihydroxyvitamin D3 on osteocalcin in postmenopausal osteoporosis. Calcif. Tissue Int. 38:328-332. Carpenter, M.P. 1986. Effects of vitamin E on the immune system. Pp. 199-211 in F.L. Meyskens, Jr., and K.N. Prasad, eds. Vitamins and Cancer. Humana Press, Clifton, N.J. Chlebowski, R.T., J.B. Block, M. Dietrich, E. Octay, N. Barth, R. Yanagihara, C. Gota, and I. Ali. 1983. Inhibition of human tumor growth and DNA biosynthetic activity by vitamin K and warfarin: in vitro and clinical results. Proc. Am. Assoc. Cancer Res. 24:165. Chlebowski, R.T, M. Dietrich, S.A. Akman, and J.B. Block. 1984. Vitamin K3 (menadione) inhibition of human tumor growth in the soft agar assay system. Proc. Annu. Meet. Am. Soc. Clin. Oncol. 3:93. Christiansen, C., and P. Rødbro. 1984. Serum vitamin D metabolites in younger and elderly postmenopausal women. Calcif. Tissue Int. 36:19-24. Colditz, G.A., L.G. Branch, R.J. Lipnick, W.C. Willett, B. Rosner, B.M. Posner, and C.H. Hennekens. 1985. Increased green and yellow vegetable intake and lowered cancer deaths in an elderly population. Am. J. Clin. Nutr. 41:32-36. Constantinides, P., and M. Harkey. 1985. Initiation of a transplantable fibrosarcoma by the synergism of two noninitiators, alpha-tocopherol and soya oil. Virchows Arch. Pathol. Anat. 405:285-297. Corrigan, J.J., Jr., and F.I. Marcus. 1974. Coagulopathy associated with vitamin E ingestion. J. Am. Med. Assoc. 230:1300-1301. Corrigan, J.J., M. Jeter, and D.L. Earnest. 1982. Prothrombin antigen and coagulant activity in patients with liver disease. J. Am. Med. Assoc. 248:1736-1739. Crilly, R.G., A. Horseman, M. Peacock, and B.E. Nordin. 1981. The vitamin D metabolites in the pathogenesis and management of osteoporosis. Curr. Med. Res. Opin. 7:337-348. Davies, R.E. 1967. Effect of vitamin A on 7,12-dimethylbenz(alpha)anthracene-induced papillomas in rhino mouse skin. Cancer Res. 27:237-241. DeLuca, H.F. 1979. Vitamin D: Metabolism and Function. Monographs on Endocrinology, Vol. 13. Springer-Verlag, Berlin. 80 pp. DeLuca, H.F. 1981. Recent advances in the metabolism of vitamin D. Annu. Rev. Physiol. 43:199-209. DeLuca, H.F. 1988. The vitamin D story: a collaborative effort of basic science and clinical medicine. FASEBJ. 2:224-236. DeLuca, H.F., R.T. Franceschi, B.P. Halloran, and E.R. Massaro. 1982. Molecular events involved in 1,25-dihydroxyvitamin D3 stimulation of intestinal calcium transport. Fed. Proc. 41:66-71. Deutsch, E. 1965. Blood coagulation changes in liver disease. Prog. Liver Dis. 2:69-83. DHHS/USDA (Department of Health and Human Services/ U.S. Department of Agriculture). 1986. Nutrition Moni-
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Page 324 toring in the United StatesA Progress Report from the Joint Nutrition Monitoring Evaluation Committee. DHHS Publ. No. (PHS) 86-1255. National Center for Health Statistics, Public Health Service, U.S. Department of Health and Human Services, Hyattsville, Md. 356 pp. Dimitrov, N.V. 1986. Beta-carotene: biological properties and applications. Pp. 167-202 in J. Bland, ed. 1986: A Year in Nutritional Medicine, 2nd ed. Keats Publishing, New Canaan, Conn. Donegan, C.K., A.L. Messer, E.S. Orgain, and J.M. Ruffin. 1949. Negative results of tocopherol therapy in cardiovascular disease. Am. J. Med. Sci. 217:294-299. Epstein, J.H. 1977a. Chemicals and photocarcinogenesis. Australas. J. Dermatol. 18:57-61. Epstein, J.H. 1977b. Effects of beta-carotene on ultraviolet induced cancer formation in the hairless mouse skin. Photochem. Photobiol. 25:211-213. Epstein, J.H., and D.A. Grenkin. 1981. Inhibition of ultraviolet-induced carcinogenesis by all-trans retinoic acid. J. Invest. 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