The water-soluble vitamins include ascorbic acid (vitamin C), thiamin, riboflavin, niacin, vitamin B6 (pyridoxine, pyridoxal, and pyridoxamine), folacin, vitamin B12, biotin, and pantothenic acid.
Dietary Sources, Patterns of Intake, and Levels of Water-Soluble Vitamins
Vitamin C is active in the body either as L-ascorbic acid or as dehydroascorbic acid. Its best-known function is as a cofactor for the enzyme required to hydroxylate prolyl and lysyl residues for the synthesis of connective tissue proteins. The 1980 Recommended Dietary Allowance (RDA) for adults60 mg/daymaintains a body pool of 1.5 g, whereas 10 mg/day is sufficient to prevent or cure scurvy (NRC, 1980).
Since the beginning of the century, the amount of vitamin C in the food supply has increased, partly because of the greater supplies of citrus fruits and dark-green vegetables and partly because of the fortification of some foods. According to the U.S. Department of Agriculture's Continuing Survey of Food Intakes of Individuals (CSFII) in 1985 (USDA, 1987), the mean vitamin C intake for children 1 to 5 years of age was 187% of the RDA, and for women 19 to 50 years of age, it was 125% of the RDA, based on 4 nonconsecutive days of intake. For men 19 to 50 years of age, the mean intake was 207% of the RDA (USDA, 1986), based on a 1-day intake.
NHANES IIthe National Health and Nutrition Examination Survey, conducted from 1976 to 1980indicated that 3% of the respondents 3 to 74 years of age had low serum vitamin C levels. Therefore, the Joint Nutrition Monitoring Evaluation Committee concluded that this vitamin should be accorded high-priority status for future monitoring (DHHS-USDA, 1986).
The Nationwide Food Consumption Survey (NFCS) of 1977-1978 indicated that 73% of the vitamin C intake came from fruits and vegetables. Mean intakes of vegetables and fruits were decidedly less for women and children under 131% of the poverty level on the basis of 4 nonconsecutive days of intake in 1985 (USDA, 1987).
The highest levels of vitamin C are found in green peppers, broccoli, citrus fruits, strawberries, melons, tomatoes, raw cabbage, and leafy greens such as spinach, turnip, and mustard greens. Losses of vitamin C occur when foods are cooked in large amounts of water, exposed to extensive heating, or exposed to air.
Thiamin functions in the body in the form of thiamin pyrophosphate (TPP), the coenzyme for
the transfer of active aldehyde in carbohydrate metabolism and decarboxylation of a-keto acids such as pyruvate. The requirement for thiamin is directly correlated with carbohydrate intake and increases as the metabolic rate increases due to pregnancy, lactation, or increased physical exercise. The 1980 RDA of 0.5 mg/1,000 kcal was set to maintain normal levels of TPP-dependent erythrocyte transketolase activity and urinary excretion. For those whose total caloric intake is less than 2,000 kcal, at least 1.0 mg/day is recommended.
NFCS data for 1977-1978 indicate that 83% of all respondents consumed 70% or more of the thiamin RDA (USDA, 1984). Men and women 19 to 50 years of age in the 1985 survey averaged 0.70 mg/1,000 kcal, whereas children 1 to 5 years old averaged 0.79 mg/1,000 kcal (USDA, 1986, 1987).
In its coenzyme forms (flavin mononucleotide and flavin adenine dinucleotide), riboflavin functions in oxidation-reduction reactions in energy production, in the respiratory chain, and in many other metabolic pathways. Richest food sources of riboflavin include liver, milk, dark-green leafy vegetables, and enriched breads and cereals.
The 1980 RDA for riboflavin is 0.6 mg/1,000 kcal; a minimum of 1.2 mg/day is recommended for those whose caloric intake is less than 2,000 kcal/day. In 1985 the mean intake for men and women 19 to 50 years of age was 0.82 mg/1,000 kcal and 0.88 mg/1,000 kcal, respectively (USDA, 1986, 1987); for children 1 to 5 years of age, it was 1.12 mg/1,000 kcal (USDA, 1987). Food groups contributing the most riboflavin to diets of women and children in the 1985 and 1986 surveys were enriched grain products, milk and milk products, meat, poultry, and fish.
In nutrition literature, the term niacin is used generically to encompass the active forms of this vitamin, nicotinic acid and nicotinamide; however, estimates of niacin requirements take into account preformed niacin as well as that obtained as equivalent (NE) in the body from tryptophan metabolism. For this purpose, it is estimated that when 60 mg of tryptophan are consumed by an adult, enough is oxidized to produce 1 mg of niacin (NRC, 1980).
Hundreds of enzymes in the body require niacin in its coenzyme forms nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Many reactions utilizing these enzymes are involved in energy metabolism. Hence, the 1980 RDA is set at 6.6 niacin equivalents (NE) per 1,000 kcal, and an intake of not less than 13 NE is recommended when the caloric intake is less than 2,000 kcal. One NE is equal to either 1 mg of niacin or 60 mg of tryptophan.
The 1985 CSFII indicated that the mean intake of preformed niacin for women (USDA, 1987) and men (USDA, 1986) 19 to 50 years was 10.8 NE/1,000 kcal, whereas for children 1 to 5 years it was 9.6 (USDA, 1987). Average diets in the United States have been estimated to furnish 500 to 1,000 mg or more of tryptophan per day, providing 8 to 17 NE (NRC, 1980). Grain products, meat, poultry, and fish were the most important sources of preformed niacin reported in the 1985 and 1986 CSFII; nuts and legumes were identified as good sources.
Vitamin B6 is the generic term used for pyridoxine, pyridoxal, and pyridoxamine, the coenzyme forms of which are pyridoxal phosphate and pyridoxamine phosphate. Vitamin B6-dependent enzymes are needed in a wide range of reactions, most of which involve amino acid metabolism. The 1980 RDAs were based on a ratio of 0.02 mg of vitamin B6 per gram of protein consumed. The allowance for adult females was therefore set at 2.0 mg/day, assuming a protein intake of 100 g/day; for adult males, it was set at 2.2 mg/day, assuming a protein intake of 110 g/day. A lower allowance presumably would be appropriate for those with lower protein intakes.
A major difficulty in assessing vitamin B6 intake is that values for the B6 content of food are unreliable. In the 1977-1978 NFCS, on the 3 days studied, 72% of the respondents consumed at least 80% of the desired ratio of vitamin B6 to protein, whereas only 39% had at least 80% of the vitamin B6 RDA. The 1985 CSFII indicated that on the 1 day surveyed, men 19 to 50 years of age on average consumed 85% of the B6 RDA, but that only 27% of women consumed 70% or more of their B6 RDA (USDA, 1986, 1987). However, the mean ratio of vitamin B6 to protein was 0.019 for women, despite the fact that 43% of them consumed less than 50% of the RDA (USDA, 1987). Failure to
meet the RDA does not denote a deficient diet because actual requirements differ in a population (see Chapter 3). Women in lower income groups had lower intakes of vitamin B6 than did those of higher income brackets. The major food sources of vitamin B6 in those surveys were meats, poultry, fish, grain products, fruits, and vegetables. More research is needed on the adequacy of vitamin B6 intake and the nutritional status of the population for this vitamin (DHHS-USDA, 1986).
Vitamin B12 substances are physiologically active cobalamins. The coenzyme (5'-deoxyadenosyl) and methyl forms of this vitamin are essential for the recyling of the active folate coenzyme, for the methylation of homocysteine to form methionine, and for metabolism of propionate. Vitamin B12 is also essential in the metabolism of fatty acids and aliphatic amino acids through its role in the isomerization of methylmalonyl-CoA to succinyl-CoA.
Vitamin B12 is synthesized by bacteria and is found only in animal foods such as meats, milk and milk products, and eggs. The 1980 RDA is 3 µg/day for individuals 7 years of age and older. National surveys indicate that intakes are higher for males than for females and higher for those in higher economic groups. The 1985 CSFII indicated that 60% of women 19 to 50 years of age consumed 100% of the RDA or more (USDA, 1987).
Folacin (Folic Acid or Folate)
Folacin intakes have been studied very little, because values for this vitamin in food composition tables are imputed. In addition, present analytical methods for this vitamin are not very reliable. There is also some concern that the 1980 RDA for folacin is unrealistically high (DHHS-USDA, 1986).
Folacin coenzymes are essential in the body for the transfer of single carbon units. They are needed for the synthesis of purine, methionine, and thymidylate, for the catabolism of histidine, and for the conversion of serine to glycine. The metabolism of folacin and vitamin B12 is linked because normal activity of methyl vitamin B12 is needed to maintain the metabolically active form of folacin.
The 1980 RDA was set at 400 µg/day for persons 11 years of age and older. The first national survey to report folacin intakes was CSFII in 1985. Women 19 to 50 years of age had average intakes of 189 µg/day (USDA, 1987), whereas intakes for men 19 to 50 years of age averaged 305 µg/day (USDA, 1986). On the basis of limited data, women 20 to 44 years of age were reported in NHANES II to be at greatest risk for folacin deficiency (Senti and Pilch, 1984).
The Joint Nutrition Monitoring Evaluation Committee accorded high priority to monitoring the status of vitamin C, because of some low serum values reported in NHANES II and concluded that thiamin, riboflavin, and niacin warrant continued monitoring. That committee also recommended further investigation of the relationship between dietary intakes and nutritional status for both vitamin B6 and folacin (DHHS-USDA, 1986).
Following is the evidence relating water-soluble vitamins to chronic diseases.
Evidence Associating Water-Soluble Vitamins with Chronic Diseases
In epidemiologic studies, the association of vitamin C with cancer is mostly indirect, since it is based on the consumption of foods known to contain high or low concentrations of the vitamin rather than on measured ingestion of ascorbic acid.
Meinsma (1964) noted that the consumption of citrus fruits by persons with gastric cancer was lower than that by controls. Similar inverse associations between fresh fruit consumption or vitamin C intake and gastric cancer were reported by Bjelke (1978), Higginson (1966), Haenszel and Correa (1975), and Kolonel et al. (1981). In a case-control study of stomach cancer conducted in Canada, Risch et al. (1985) found that citrus fruit intake was somewhat protective (odds ratio 0.75 per 100 g daily average intake). In a univariate analysis, vitamin C intake was significantly (p = .0056) protective against stomach cancer. Risch and colleagues analyzed vitamin C intake from 21 common vegetables along with the intake of nitrate and found that vitamin C consumption had a strong and highly protective effect. In a multiple logistic regression model, however, vitamin C intake did not make a significant contribution to risk reduction beyond a protective effect found for dietary fiber. This could partly be explained by the correlation between the sources of vitamin C and dietary fiber.
Mettlin et al. (1981) found inverse associations of indices of vitamin A and vitamin C consump-
tion with esophageal cancer based on frequency of consumption of selected food items by male cases and controls. The relationship was stronger for vitamin C than for vitamin A, and only the association with vitamin C was statistically significant after controlling for smoking and alcohol use.
In studies of esophageal cancer in the Caspian Littoral of Iran, inverse associations were found between esophageal cancer and consumption of fresh fruits and estimated vitamin C intake based on correlational and case-control data (Cook-Mozaffari, 1979; Cook-Mozaffari et al., 1979; Hormozdiari et al., 1975; Joint Iran-International Agency for Research on Cancer Study Group, 1977). In a study of diet and esophageal cancer conducted in the Calvados region of France, Tuyns et al. (1987b) found further evidence for a protective effect of vitamin C consumption as estimated from food data banks. The estimate of relative risk for moderate consumers of vitamin C was 0.7 and for heavy consumers, 0.4. Similar protective effects were also found for vitamin E, carotene, and some other micronutrients. It is not clear whether the results of this study reflect general nutritional deficiency, particularly in individuals with high alcohol consumption, or a more specific effect of vitamin C.
Jain et al. (1980) found no association between vitamin C consumption, also estimated from food data banks, and colon cancer in a case-control study in Canada. In a case-control study on colorectal cancer in Marseilles, Macquart-Moulin et al. (1986) found a significant protective effect of vitamin C after adjustment for age, caloric intake, and weight. The risk in the highest consumption category relative to the lowest was 0.16. In a multivariate analysis including other macro- and micronutrients, however, vitamin C was no longer significantly protective. The effect of vitamin C was also evaluated in two case-control studies of colorectal cancer in Australia. In one (Potter and McMichael, 1986), vitamin C consumption was associated with a reduced relative risk for rectal cancer in males and females (ages 30-74 years), especially for younger males; the effect disappeared by 70 years of age. No protective effect was found for colon cancer. In another case-control study, conducted in Belgium by Tuyns et al. (1987a), there was no indication of a protective effect of vitamin C.
The effect of vitamin C has also been assessed in several studies of other cancer sites. In a case-control study of laryngeal cancer, Graham et al. (1981) found an inverse relationship between risk and indices of both vitamin C and vitamin A consumption after controlling for cigarette smoking and alcohol consumption. There was a similar relationship for vegetable consumption in general. Wassertheil-Smoller et al. (1981) reported an association between vitamin C consumption and uterine cervical dysplasia in a case-control study in New York. The findings persisted after the investigators controlled for sexual activity. Stähelin et al. (1984) evaluated plasma vitamin C in a cohort of more than 4,000 men primarily studied for the risk of cardiovascular disease. Plasma vitamin C was found to be consistently lower in cancer cases than in controls. The largest differences were for cancers of the lung and stomach. Böing et al. (1985) analyzed regional nutritional data from a national survey on income and food consumption in the Federal Republic of Germany and correlated mortality rates with the food consumption data for 15 nutrients. Significant positive correlations were found between vitamin C and cancers of the breast, prostate, liver, and colon. In a case-control study of lung cancer in Hawaii, however, Hinds et al. (1984) found no association between dietary vitamin C intake and lung cancer risk.
Ascorbic acid has been reported to prevent the formation of N-nitroso compounds (Mirvish, 1981a; Tannenbaum and Mergens, 1980). Vitamin C is postulated to act by the reduction of nitrite, ultimately preventing formation of nitrosamine or nitrosourea as demonstrated in vitro. (For a review, see Mirvish, 1981b.)
Abdel-Galil (1986) investigated the effect of ascorbic acid given in drinking water on local methylcholanthrene-induced sarcomas in mice and found that test animals had fewer sarcomas compared to the controls. Vitamin C supplementation, however, did not reduce the diameters or weights of the tumors.
Pauling et al. (1985) studied the effect of varying amounts of L-ascorbic acid (between 0.076% and 8.3% of total diet) on the incidence of spontaneous tumors in RIII mice. They reported that as the amount of ascorbic acid in the diet increased, there was a large decrease in the first-order rate constant. Other studies by the same researchers indicated that increased levels of dietary vitamin C delayed the onset of dermal neoplasms induced in hairless mice by ultraviolet (UV) light (Cameron and Pauling, 1979; Pauling et al., 1982). Dunham et al. (1982) also showed that skin carcinogenesis (squamous cell carcinomas and papillomas) in UV light-treated mice was inhibited by vitamin C.
Male Syrian hamsters taking vitamin C supplements were exposed to cigarette smoke and subcutaneous injections of diethylnitrosamine (DEN) (Harada et al., 1985). In comparison with the unsupplemented smoke-exposed hamsters treated with DEN, the vitamin C-supplemented group had a lower incidence of nasal cavity tumors, but tracheal and laryngeal tumors appeared sooner. These results suggest that vitamin C supplementation accelerates the development of certain cancers and inhibits induction at other sites.
The ability of vitamin C (in drinking water) to inhibit induction of renal carcinoma by estrogens was examined in Syrian hamsters (Liehr and Wheeler, 1983). The incidence of renal carcinoma in the vitamin C-supplemented group was considerably lower than in the nonsupplemented group. High doses of vitamin C (525 mg/day) provided in drinking water to Wistar rats largely inhibited benzo[a]pyrene-induced malignant tumors (Kallistratos and Fasske, 1980).
Silverman et al. (1983) explored the possible inhibitory effect of vitamin C (sodium ascorbate) on metastases from two transplantable murine tumors in male Balb/c mice. There was no difference in survival rates or in the number or size of metastases between the treated and control groups. In fact, brain and regional lymph node metastases appeared to be enhanced by ascorbic acid. Divergent effects of vitamin C were also observed in colon carcinogenesis by dimethylhydrazine (DMH) in the rat. Results from Reddy et al. (1982) indicate that 2 to 10 g of vitamin C per kilogram of diet inhibited carcinogenesis, whereas enhancement of carcinogenesis was observed in another study in which vitamin C was administered to Fischer 344 rats at 50 g/kg diet (Shirai et al., 1985). The incidence of DMH-induced large bowel neoplasms was reduced in mice that consumed a diet containing <0.5 g of vitamin C/kg (Jones et al., 1984).
In another study, methylnitrosourea (MNU)induced colon cancer in rats was not influenced by dietary vitamin C (Reddy et al., 1982). High doses of ascorbic acid administered in the drinking water had no effect on the growth of transplantable mammary tumors induced by dimethylbenzanthracene in rats (Abul-Hajj and Kelliher, 1982). There was either no reduction or enhancement of subcutaneous 3-methylcholanthrene-induced tumors in scorbutic guinea pigs treated with vitamin C (Banic, 1981; Russell et al., 1952).
Vitamin C has also been observed to be a promotor of cancer. Urinary bladder carcinogenesis induced in rats by MNU or n-butyl-n-(4-hydroxybutyl)-nitrosamine (BBN) was promoted when sodium ascorbate was administered at 50 g/kg body weight (Fukushima et al., 1983; Imaida et al., 1984). However, in another study ascorbic acid fed at the same level was observed to have no effect on BBN-induced cancer (Fukushima et al., 1984). The authors speculated that the sodium salts of certain organic acids act as promoters of urinary bladder cancer.
In short-term tests, Krishna et al. (1986) found that ascorbic acid per se did not affect sister chromatid exchanges (SCEs) induced by cyclophosphamide (CPA) and mitomycin E (MME) in bone marrow and spleen cells in mice in vivo. However, increasing concentrations of ascorbic acid caused decreasing levels of CPA- and MME-induced SCEs in both types of cells in vivo.
Atherosclerosis and Coronary Heart Disease
An association between vitamin C and atherosclerosis has been suggested in studies that evaluated the relationship between vitamin C and cholesterol. Dubick et al. (1987) found ascorbic acid levels to be low in tissue samples from 29 patients with abdominal aortic aneurysms and 14 patients with atherosclerotic occlusive disease. Spittle (1972) found that in healthy people under the age of 25, cholesterol levels tended to fall when 1 g of vitamin C per day was added to an otherwise normal diet. In older people, no consistent pattern of serum cholesterol change was seen. Ramirez and Flowers (1980) compared the ascorbic acid level of leukocytes in patients with coronary heart disease (CHD) to that in patients without CHD, as demonstrated by coronary arteriography. Leukocyte ascorbic acid levels were found to be lower in the patients with coronary artery disease. Mayet et al. (1986) studied Indian and black South African patients with diagnoses of cardiac infarction and diabetes mellitus. They found a negative correlation between leukocyte ascorbic acid and serum cholesterol levels in Indians, especially in patients with infarctions.
Beetens et al. (1984, 1986) reported that a low dose of vitamin C added to a cholesterol-rich diet given to rabbits decreased lipid infiltration and intimal thickening. Altman et al. (1980) found that vitamin C, especially when associated with
phospholipids, led to prevention or resolution of atheromatous plaques provoked in rabbits by cholesterol feeding.
The B VitaminsThiamin
De Reuck et al. (1980) observed severe thiamin deficiency (Wernicke's encephalopathy) in patients with tumors of the lymphoid-hematopoietic system. Since all the patients had gastrointestinal bleeding, hepatic failure, and sepsis, the authors suggested that malabsorption was a probable cause of the thiamin deficiency. Hence, there is probably no direct relationship between thiamin deficiency and tumorigenesis. Rather, thiamin deficiency may be a secondary event related to malnutrition.
The committee was unable to identify any laboratory studies of thiamin and cancer.
In the United States, clinical thiamin deficiency is usually the result of alcoholism. The relation between thiamin deprivation and caloric intake appears to determine whether the deficiency is expressed as beriberi, Wernicke's encephalopathy, Korsakoff's syndrome, or alcoholic polyneuritis (Alpers et al., 1983; Schenker et al., 1980). There is no abnormality in the proportion of phosphorylated species of thiamin to total thiamin in well-nourished alcoholics, and the thiamin levels in their organs are maintained (Dancy et al., 1984; Hoyumpa, 1983).
Alcohol has multiple effects on thiamin nutriture. Hepatic storage of thiamin may be reduced due to fatty infiltration of the liver, decreased functional liver mass, or other liver pathology. The mechanism of action is still not clear.
More than 30 years ago, Wynder et al. (1957) observed that Plummer-Vinson disease, often associated with esophageal cancer, was linked with riboflavin deficiency. More recently, diets marginal or deficient in riboflavin, nicotinic acid, magnesium, and zinc have been correlated with esophageal cancer (Thurnham et al., 1982; van Rensburg et al., 1986).
Riboflavin deficiency has also been reported to cause possibly precancerous lesions in the esophageal epithelium of humans (Foy and Mbaya, 1977). However, substances other than riboflavin (e.g., alcoholic beverages or nassa chewing tobacco product) that contain N-nitroso compounds may contribute independently to the development and progression of esophageal cancer. Low levels of riboflavin, vitamin A, and carotenoids have been found in a population with a high incidence of oral and esophageal cancer (Zaridze et al., 1985). A remarkably high proportion (41%) of the men surveyed were users of nass. The authors suggest that since low levels of riboflavin, vitamin A, and carotenoids were associated with a high incidence of certain cancers, higher levels of these nutrients may have a protective effect against the development of cancer.
Esophageal cancer and riboflavin deficiencies are widespread in Africa, Iran, and China. It has not yet been established, however, that riboflavin deficiency per se plays a role in esophageal cancer, because riboflavin metabolism may be affected by zinc status (Merrill and McCormick, 1980), and zinc deficiency is also associated with esophageal cancer.
In an endoscopic study in Linxian, Hunan Province, China, Thurnham et al. (1982) found that 97% of 527 subjects had ariboflavinosis, based on the erythrocyte glutathione reductase activity coefficients. Blood samples were collected to measure the status of riboflavin and several other nutrients in persons in certain geographic areas of China. In two surveys in China, one in Linxian County (a high-risk area for esophogeal cancer) and the other in Jiaoxian County (a low-risk area), the distribution of erythrocyte glutathione reductase activity coefficient values suggested that riboflavin levels were higher in the low-risk community (Thurnham et al., 1985).
The hypothesis that riboflavin deficiencies are associated with precancerous lesions of the esophagus has been examined by Munoz et al. (1985). A population at high risk for esophageal cancer in China received weekly supplements of retinol, riboflavin, and zinc, or a placebo in a randomized double-blind intervention trial. No differences in the prevalence of esophagitis with or without atrophy or dysplasia were noted in the two groups examined at 13 months. It is not known if different
results would have been obtained if the study had been continued.
Male baboons fed a diet lacking riboflavin developed cutaneous lesions, including hyperkeratosis, gross derangement of keratinization with acanthosis, and impressive pseudocarcinomatous hyperplasia (Foy and Kondi, 1984). The esophageal epithelium was thin and pale in some of the animals, and there was esophagitis and large, chronic, disorganized lesions. The numerous mitotic figures that were commonly encountered were distinguishable from carcinomas only by their disorganized, highly active epithelial growth and by the absence of muscular invasion. Foy and Kondi (1984) noted that this condition may reflect a precursor state that could take years to become invasive.
Rats were fed test diets supplemented with low doses of riboflavin, nicotinic acid, zinc, magnesium, selenium, and molybdenum for 45 days, dosed with N-nitroso-methylbenzylamine (3 mg/kg), and then continued on the test diets for 150 days (van Rensburg et al., 1986). Compared to controls, the supplemented group had fewer tumors (esophageal carcinomas) and tumor-bearing animals. These results indicate that low doses of supplements are helpful in the treatment of premalignant esophageal changes. The effects of high doses of supplements are unknown. The findings of that study, however, are most likely relevant to early prevention of esophageal cancer, since supplementation was started 45 days before dosing with the carcinogen.
Kensler et al. (1941) noted a relationship between the consumption of riboflavin and susceptibility to carcinoma induced by dimethylaminoazobenzene. Numerous studies have confirmed this general phenomenon. (For reviews see Bidlack et al., 1986; Miller and Miller, 1953; Rivlin, 1975). Bidlack et al. (1986), for example, reported that riboflavin deficiency adversely affects liver detoxification mechanisms. In addition, reduced nicotinamide dinucleotide phosphate (NADPH)cytochrome P-450 reductase activity is decreased, as is the metabolism of aniline, acetaniline, aminopyrine, and ethylmorphine. Riboflavin deficiency appears to increase susceptibility to abnormal processing of potential carcinogens. Lee et al. (1983) found that riboflavin deficiency in rats only modestly decreased cytochrome P-450 but markedly decreased peroxisomal flavoprotein oxidases, which produce hydrogen peroxide; a decrease in liver catalase followed.
Cancer patients frequently metabolize riboflavin in aberrant ways. They excrete lower than normal levels of riboflavin in the urine (Kagan, 1960) and do not excrete larger amounts after oral or intravenous doses (Kagan, 1957, 1960). Riboflavin may be trapped by the tumor or the host. Baker et al. (1981) found that samples of colon adenocarcinoma obtained at autopsy contained nearly twice as much riboflavin and elevated amounts of other water-soluble vitamins as did neighboring tissue. However, liver adenocarcinomas were found to contain about the same levels as liver tissue from controls (and smaller amounts of several other vitamins such as B12). Innis et al. (1985, 1986) reported that immunoglobulins are the major proteins responsible for riboflavin binding in human plasma and that their levels are higher in patients with breast cancer and melanoma. The lower urinary levels and clearance in cancer patients could be due in part to increased plasma binding rather than trapping by tumor tissue.
Ethanol consumption can reduce intestinal bioavailability of riboflavin, particularly flavin adenine dinucleotide (FAD) (Pinto et al., 1984). The accumulation of fat in the liver in riboflavin-deficient persons resembles changes observed in the liver of chronic alcoholics. In humans with liver cirrhosis, decreased concentrations of riboflavin are found mostly in necrotic regions (Chen and Liao, 1960). Riboflavin deficiency is usually encountered when there is a general lack of B vitamin intake, such as in forms of malnutrition that accompany alcoholism. Changes in the activities of flavoproteins and other hepatic enzymes result from riboflavin deficiency, but it is not known whether all these changes can be fully reversed after supplementation with riboflavin.
Hepatic concentrations of FAD were reported to be one-third the normal level in rats fed diets deficient in riboflavin (Fass and Rivlin, 1969). Flavokinase activity in rats fed riboflavin-free diets was decreased to about 40% of normal. Riboflavin deficiency has selective effects on the activities of liver enzymes involved in riboflavin metabolism (Lee and McCormick, 1983). It appears to have
the greatest effect on flavokinase, which is physiologically rate-limiting in the biosynthesis of flavocoenzymes.
Riboflavin deficiency in mice alters hepatic architecture, including enlargement and distortion of mitochondria, possibly due to defects in oxidative phosphorylation resulting from lack of flavoproteins (Burch et al., 1960; Tandler et al., 1968). Decreased mitotic activity has been observed in fetal liver of the offspring of riboflavin-deficient dams (Miller et al., 1962).
Warwick and Harington (1973) noted that the incidence of pellagra also often increases in geographic areas where esophageal cancer is becoming more frequent. The authors cautioned, however, that pellagra may reflect an extreme deficiency of niacin complicated by deficiencies of other vitamins and minerals such as riboflavin, magnesium, and zinc. The predisposition to esophageal cancer and cancer of other sites may be due to damaging effects of these deficiencies on the organs (Thurnham et al., 1982; van Rensburg et al., 1986).
Diets low in protein (5.5%) and high in carbohydrates were used to test the effect of 0, 50, or 500 mg of nicotinamide per kilogram of diet on N-nitrosodimethylamine-induced carcinogenesis in Holtzman albino rats (Miller and Burns, 1984). Both the oxidized and the reduced forms of NAD and NADP were found in lower concentrations in the livers of test animals than in controls. In the kidney, only NADH and NADPH were below normal. After 5 weeks of treatment, all the animals were returned to a standard diet for 85 weeks. The investigators reported that the initial diets had no effect on tumor incidence or tumor type. These results suggest that nicotinamide does not exert a long-term effect on tumorigenesis.
Schoental (1977) reported an increased incidence of kidney neoplasms in rats given nicotinamide (300 to 500 mg/kg of body weight) intraperitoneally before and after each dose of DEN. Rosenberg et al. (1985) reported that nicotinamide (6.7 or 30 mM) in the drinking water of male Fischer 344 rats also receiving DEN (25 mg/kg by intraperitioneal injection) caused a 28 to 59% increase in the incidence of kidney tumors. There was a 5% incidence of kidney tumors in rats treated with DEN alone, whereas no kidney tumors were found in rats given nicotinamide alone. Grassetti (1986) noted that several analogs of niacin (sulfur-containing, 5- and 6-membered, heterocyclic carboxylic acids) decreased the number of pulmonary metastases in C57B/6 mice implanted with Lewis lung carcinoma. These niacin compounds also inhibited the growth rate of the primary implanted tumor by 50%.
These conflicting results suggest that niacin may be a carcinogen or a cocarcinogen, or it may inhibit carcinogenesis. The precise effect of niacin appears to be influenced by the dose and nature of the niacin compound, time and site of administration, nature of the carcinogen, and type of tumor. For example, in some systems, nicotinamide increased the incidence of tumors of the pancreas but decreased the incidence of kidney tumors (Rakieten et al., 1971). The effects of nicotinamide may be due to increasing the NAD pools, which are depleted by certain carcinogens (Rakieten et al., 1971; Schoental, 1975).
The human liver contains approximately 60 mg of nicotinic acid (free and covalently bound in coenzymes) per kilogram wet weightan amount similar to concentrations in other tissues (Wiss and Weber, 1964); it contains no special stores of nicotinic acid or its derivatives. In alcoholics, the degree of liver disease influences the concentrations of nicotinic acid in that organ. For example, the total nicotinic acid content of the cirrhotic liver can fall as low as 80% of normal values (Baker et al., 1964; Jusko and Levy, 1975). The increase in liver lipid content caused by ethanol administration can be reversed by administration of nicotinic acid (Baker et al., 1976), which inhibits the peripheral release of free fatty acid and liver alcohol dehydrogenase. These studies suggest that the condition of the liver influences nicotinic acid concentrations.
A high nicotinic acid intake has been associated with hepatotoxicity. One-third to one-half of patients taking 3 g of nicotinic acid per day for 5 years had elevated levels of serum glutamic oxaloacetic transaminase (SGOT) and alkaline phosphatase (Coronary Drug Project Research Group,
1975; DiPalma and Ritchie, 1977; Einstein et al., 1975). (The RDA for niacin is 18 mg for males and 13 mg for females.)
Niacin may increase serum uric acid levels (APA, 1973; Coronary Drug Project Research Group, 1975; Ivey, 1979). In the Coronary Drug Project Group (1975), patients on niacin had an increased incidence of acute gouty arthritis and a decrease in nonfatal recurrent myocardial infarction, but there was no decrease in total mortality. It was not known whether this was the result of the cholesterol-lowering effect of nicotinic acid, a direct effect of niacin, or both.
Bell (1980) reported that women with breast cancer who excrete less pyridoxic acid than average (one reflection of vitamin B6 status) have an increased probability of a recurrence of breast cancer. The physiological significance of the relationship between low excretion of pyridoxic acid and risk of recurrence is unknown. Ladner and Salkeld (1988) noted that the 5-year survival rate of patients with stage II endometrial carcinoma was increased by administering pyrodoxine.
Several groups have reported unusual levels of vitamin B6 metabolites, such as lower plasma pyridoxal 5'-phosphate (PLP), in breast cancer patients despite normal urinary pyridoxic acid (Potera et al., 1977). Chabner et al. (1970) reported low plasma PLP in patients with Hodgkin's disease, as well as abnormalities in tryptophan metabolism in these patients.
Foy et al. (1974) fed baboons pyridoxine-deprived diets either continually or intermittently for 2 to 6 years. The livers of the intermittently deprived animals developed striking changes suggesting liver neoplasia. The acutely deprived animals died within 6 to 8 months. The surviving animals had lower serum B6 values and increased tryptophan metabolites in the urine compared to controls. The authors suggest that pyridoxine deficiency may be associated with disturbances in immunologic competence.
In laboratory animals, diets deficient in pyridoxine inhibit the growth of some types of tumors (Kline et al., 1943; Mihich and Nichol, 1959; Tryfiates and Morris, 1974). Ha et al. (1984) reported that vitamin B6 deficiency affects host susceptibility to Moloney sarcoma virus-induced tumor growth in mice. However, vitamin B6 status does not affect the growth of some tumors such as spontaneous mammary tumors in strain C3H mice (Morris, 1947). DiSorbo et al. (1985) observed a 62% reduction in tumor weight, compared with controls, in mice pretreated with PLP for 2 weeks and then injected with B-16 melanoma cells. In mice with established tumors, a 39% reduction in tumor growth was observed when the animals were treated with PLP for 6 days. The exact mechanism by which PLP exerts its inhibitory effect was not determined; however, the authors suggest that vitamin B6 may act on the plasma membrane to reduce precursor transport into the cell.
Vitamin B6 is involved in the synthesis of DNA bases; it is a coenzyme in the biosynthesis of thymidine. According to Prior (1985), a dietary B6 deficiency or an increase in the thymidine requirement at a critical time during cell division could result in initial cell mutations that develop into a tumor. The author suggests that dietary vitamin B6 supplementation could assist in preventing some cancers.
Although there is no consensus on the best biochemical marker for the assessment of vitamin B6 status in humans, plasma PLP is the one most frequently used (Williams et al., 1984). Most dietary vitamin B6 is rapidly converted by the liver to this active coenzyme form, which has a central role in the metabolism of amino acids.
As measured by PLP levels in plasma, vitamin B6 deficiency can occur in as many as 30 to 50% of alcoholics without liver disease and in 80 to 100% of those with liver damage (Frank et al., 1971; Spannuth et al., 1978). Inadequate intake may not be the only factor contributing to low plasma levels of PLP. Lumeng and Li (1974) suggest that PLP in erythrocytes is destroyed more rapidly in the presence of acetaldehyde, the first product of ethanol oxidation, perhaps by displacement of PLP from protein and its exposure to phosphatase. Low plasma levels of PLP may also be due to increased breakdown or to poor absorption of dietary vitamin B6 (Zaman et al., 1986). Thus, abnormal vitamin B6 metabolism in liver disease may be due to several factors.
Liver and plasma PLP levels are considerably reduced in patients with cirrhosis and other he-
patic diseases, even when the patients are given a normal diet (Bonjour, 1980; Henderson et al., 1986; Merrill et al., 1986). In cirrhotics, plasma PLP response to administered pyridoxine is impaired (Henderson et al., 1986; Spannuth et al., 1978). Mitchell et al. (1976) reported that PLP administered intravenously is cleared more rapidly by patients with liver disease than by controls. Cirrhotics are capable of apparently normal PLP synthesis but have increased hepatic dephosphorylation, which may be responsible for low plasma levels of PLP (Merrill and Henderson, 1987; Merrill et al., 1986). This is associated with elevated alkaline phosphatase in the plasma of these patients (Anderson et al., 1980). Attempts to normalize plasma PLP in cirrhotics have had limited success.
Shane (1982) found that rats receiving approximately 30% of their calories from ethanol metabolized pyridoxine relatively normally and their tissue stores were not decreased. There was, however, an increase in hepatic PLP. In histological examinations, no evidence of liver damage was found. These results differ from most observations reported in human subjects and cannot be fully explained.
In a randomized trial, Butterworth et al. (1982) administered oral folic acid (10 mg) or ascorbic acid (10 mg) to 87 women with cervical cancer. Their results suggest that oral folate supplements may prevent the progression of cervical dysplasia or promote regression to normalcy.
An increased incidence of tumors in the liver, colon, and esophagus results from diets deficient in methyl groups (Ghoshal and Farber, 1984; Hoover et al., 1984; Lombardi and Shinozuka, 1979; Mikol et al., 1983; Rogers, 1975). Feeding rats a diet deficient in lipotropes (choline, methionine, folate) and vitamin B12 for 15 weeks was found to increase the incidence of hepatic tumors after a single dose of diethylnitrosamine (Hoover et al., 1984).
It has long been recognized that folic acid inhibits tumor growth (Prentice et al., 1985). Early studies in mice by Leuchtenberger et al. (1945) showed inhibition of spontaneous breast tumors by folate. More recently, Rogers and Newberne (1980) showed that diets deficient in lipotrope and high in fat enhance chemical hepatocarcinogenesis in rats. Severe lipidosis and cell death result from methyl group-deficient diets (Ghoshal et al., 1983; Giambarresi et al., 1982; Shinozuka and Lombardi, 1980).
Folate deficiency in alcoholics is likely to be caused by impaired intestinal uptake as well as by decreased storage in the damaged liver (Halsted and Tamura, 1979; Hillman, 1980). Leevy et al. (1970) observed a 60% reduction in total liver folate concentration in cirrhotics, while the hepatic intake of 3H-labeled folate in moderate-to-severe cirrhotics was only 10% that of the normal liver. Moreover, administration of nonradioactive folate caused a 10-fold greater displacement of the radioactive form of this vitamin in patients with cirrhosis as compared to subjects with a normal liver. Vitamin therapy also is not successful in raising folacin levels during active necrosis or cirrhosis. Other studies in humans and animals have failed to confirm that alcohol can affect the uptake, storage, reduction, or methylation of labeled folate (Brown et al., 1973; Lane et al., 1976; McGuffin et al., 1975). Lane et al. (1976) suggest that the blocked release of tissue folate stores may result from the rapid depression of serum methyltetrahydropteroylglutamate levels and early induction of megaloblastic erythropoiesis, which has been observed following acute alcohol ingestion. Normal as well as low liver folate levels have been found in patients with chronic hepatitis and nonalcoholic cirrhosis (Kimber et al., 1965; Klipstein and Lindenbaum, 1965; Wu et al., 1975).
Alcoholic cirrhotics can develop megaloblastic anemia due to folate deficiency (Hillman, 1975). Inadequate retention of folate in the liver as well as low dietary intake of folate may contribute to this condition. Healthy subjects receiving a folate-free diet develop megaloblastic anemia after about 22 weeks (Herbert et al., 1963), whereas chronic alcoholics show a similar hematologic picture within 5 to 10 weeks (Eichner and Hillman, 1971; Halstead et al., 1973). Malnourished alcoholics (without liver disease) absorb folic acid less well than their better nourished counterparts (Halsted et al., 1971). Anemia from folic acid deficiency is rare in well-nourished alcoholics (Eichner et al., 1972).
Disordered folate metabolism is also associated with viral hepatitis. An increased excretion of urinary folate due to release of stored folates from the liver has been reported (Retief and Huskisson, 1969; Tamura and Stokstad, 1977). These data suggest that low liver folate levels in alcoholics may be due to some combination of decreased intake, decreased absorption, or increased excretion.
Kaplan and Rigler (1945) found that patients with pernicious anemia have a higher incidence of gastric carcinoma. This association was confirmed and expanded to other types of cancer, including leukemias, erythremic myelosis, polycythemia vera, and multiple myeloma (Arvanitakis et al., 1979). Ruddell et al. (1978) suggested that the increased gastric cancer risk could be caused by the intragastric formation of carcinogenic N-nitroso compounds. The concentrations of gastric nitrite are increased when the gastric acidity is decreased, as in persons with pernicious anemia. Ahmann and Durie (1984) caution that leukemia can be accelerated by the excessive replacement of vitamin B12 in patients with pernicious anemia.
Carmel and Eisenberg (1977) studied 139 patients with several types of malignancies (28 breast, 19 colon, 17 stomach, 12 lung, 8 pancreas, 8 prostate, 8 ovary, and some less prevalent sites) and found that serum levels of vitamin B12 and B12-binding proteins were elevated frequently in malignancies other than granulocytic proliferation or hepatic tumors, as had been suggested by other studies (e.g., Carmel, 1975). No correlation between serum vitamin B12 and small-cell lung cancer was found by Clamon et al. (1984).
Brain, heart, and lung tumors were found by Sheppard et al. (1984) to have higher cobalamin-binding as well as unsaturated cobalamin-binding capacity, whereas the liver tumors had an increased unsaturated cobalamin-binding capacity and a reduced total binding capacity. The results for liver cancer are consistent with the observation that liver adenocarcinomas had a lower vitamin B12 content than did specimens from adjacent, uninvaded liver (Baker et al., 1981). Presently, the relationship between vitamin B12 and the etiology of various cancers is not clear.
Areekul et al. (1986) measured serum vitamin Bl2, red-cell folate, and serum vitamin B12-binding protein in 18 patients with neuroblastoma. The status of vitamin B12 in these patients was within normal limits, but low serum and red-cell folate concentrations indicated that these patients were in a state of negative folate balance. Van Tonder et al. (1985) reported that unsaturated vitamin B12 binding capacity (UBBC) and vitamin B12 activity were slightly elevated in 80% of South African blacks with hepatocellular carcinoma, with and without cirrhosis. Paradinas et al. (1982) reported that only 9% of their patients with hepatocellular carcinomas had increased UBBC but that these patients survived longer than patients without increased UBBC. Serum vitamin B12 and UBBC values have been observed to be both elevated (although not dramatically) and normal in cancer patients.
Chemical carcinogenesis in the liver and sometimes other tissues of rats is enhanced by lipotrope deficiencies (Mikol et al., 1983; Rogers, 1975). Hoover et al. (1984) found that a diet deficient in choline, methionine, folate, and vitamin B12 fed to rats for 15 weeks after a single dose of diethylnitrosamine was sufficient to cause a high incidence of hepatic tumors.
The intake of ethanol affects the storage of vitamin B12 in the liver. Vitamin B12 deficiency is not common in alcoholics, as indicated by normal serum B12 levels in patients with folate deficiency, both with and without cirrhosis (Halsted et al., 1971; Herbert et al., 1963). The degree of liver pathology influences the extent to which liver vitamin B12 concentrations are decreased (Baker et al., 1964; Russell, 1979). Acute liver damage causes release of vitamin B12 into the plasma, where some of it binds to serum proteins and some remains free. Various liver diseases causing hepatic necrosis, such as viral hepatitis, cirrhosis, malignancy, and obstructive jaundice, result in decreased liver concentrations of vitamin B12 and increased plasma concentrations (Jones et al., 1957; Linnell, 1975; Wiss and Weber, 1964). In patients with acute hepatitis and necrosis, free vitamin B12 plasma levels are high, whereas the bound form is elevated during chronic liver disease (Jones et al., 1957).
Thus, it appears that liver and plasma levels of vitamin B12 can be sharply influenced by ethanol.
It is not clear how vitamin B12 supplementation will affect the levels of B12 in chronic alcoholics.
The committee did not identify any studies of humans concerning biotin and cancer.
Early investigations indicate that when biotin and avidin are given together to rats fed p-dimethylaminoazobenzene (DMAB), the possible cocarcinogenic action of biotin is arrested by its binding to avidin to form a complex (Du Vigneaud et al., 1942). Several attempts have been made to retard the growth of various types of neoplasia in human patients and animals by the administration of egg white or avidin (Kaplan, 1944; Kensler et al., 1943; West and Woglom, 1942) but none have been successful. Kline et al. (1945) fed rats DMAB with a highly purified diet containing suboptimal levels of riboflavin. They attempted to alter the effect of egg white by injecting biotin or denaturing the avidin by heat. The results suggest that the beneficial effects of egg white on hepatoma formation are independent of any egg white-biotin relationship but, rather, that they are dependent on optimal levels of riboflavin. These early observations do not appear to have been followed up with additional human or animal studies.
Biotin concentrations are higher in the liver than in other organs (Semenza et al., 1959). In the perfused livers of normal and alcohol-fed rats, ethanol did not induce the release of biotin as it did with other vitamins (Sorrell et al., 1974). In cirrhotics, even mild fatty liver infiltration reduced liver biotin levels (Baker et al., 1964). The change in frank cirrhotics was much less.
The committee did not identify any studies concerning pantothenic acid and cancer in humans.
Sodium w-methylpantothenate, an antagonist of pantothenic acid, was found by Bulovskaia (1976) to inhibit tumor growth in mice bearing transplanted tumors.
As with many other vitamins, levels of pantothenate in tumors may be higher or lower than in adjacent uninvolved tissues. Primary colon adenocarcinoma in rats was found to contain significantly more of the B vitamins, including pantothenate, than did normal colon tissue (Baker et al., 1981).
Because pantothenic acid concentrations are several times higher in the liver than in other tissues, the liver is affected by nutritional intake more than other organs. Spontaneous gross pantothenic acid deficiency in humans has seldom been described, although Olson (1984) has suggested that some symptoms, such as malaise and abdominal distress, may be related to deficiency of the vitamin. These symptoms, among others, were observed when volunteers were fed w-methylpantothenate.
Plasma levels of pantothenic acid vary in patients with diseased as well as nondiseased livers. The reason for this is unclear. Marked elevation of blood pantothenic acid was characteristic of alcoholics hospitalized with acute fatty liver (Cole et al., 1969). Leevy et al. (1960) reported that plasma pantothenic acid levels were normal in 172 alcoholics free of liver disease. Decreased pantothenic acid levels were observed in patients with cirrhotic fatty livers and even in some with normal liver function. In most cases, a nutritious diet and mobilization of liver fat caused levels to return to normal (Leevy et al., 1970).
Some Japanese populations with endemic pantothenic acid deficiency also have an increased prevalence of hypertension (Koyanagi et al., 1966). Schwabedal et al. (1985) fed a semisynthetic pantothenic acid-deficient diet to rats for 5 weeks. The rats were unilaterally adrenonephrectomized and then given standard rat chow together with 1% sodium chloride in drinking water. The rats developed hypertension; their final blood pressure values were more than 215 mm Hg.
Epidemiologic studies suggest that vitamin C-containing foods and possibly vitamin C itself either may protect against cancer or have no association with the disease. The strongest evidence for a protective effect seems to be for stomach cancer; the evidence for esophageal cancer is not as strong. Findings are contradictory for cancers of the colon, rectum, and lung. However, frequent consumption of these foods, especially those rich in b-carotene, is strongly associated with a protective effect against lung cancer (see Chapter 11). One problem in drawing conclusions about vitamin C and cancer is that the primary sources of vitamin Cfruits and vegetablesalso contain other potentially protective factors, for example, dietary fiber, whose intake is strongly correlated with the intake of vitamin C. Protective effects from other nutrients, such as vitamin A, carotenoids, and vitamin E, cannot be ruled out. In animal models, vitamin C may inhibit the induction of certain cancers, such as dermal neoplasms and renal carcinoma. Possible mechanisms of action for ascorbic acid are the blocking of nitrosamine formation and the reduction of other highly reactive endogenous compounds such as superoxide radicals.
Epidemiologic data derived primarily from China indicate that low riboflavin levels may be associated with a greater risk of esophageal cancer. These data are supported by similar results in animal studies. Moreover, low doses of riboflavin supplements given to animals have been found to be helpful in the treatment of premalignant esophageal changes.
In humans, elevated serum B12 and B12-binding protein have been associated with cancer of such sites as the breast, colon, and stomach; however, there is no clearly established relationship between vitamin B12and the etiology of various cancers. Animal studies suggest that vitamin B12 is likely to be a cocarcinogen, but the mechanism has not been clarified.
Hepatic disease is often accompanied by hypovitaminosis due to an increased need for vitamins in the face of decreased intake, intestinal malabsorption, and reduced hepatic storage capacity. Liver dysfunction can also prevent conversion of vitamins into their metabolically useful forms. Vitamin B complex depletion is common in hepatocellular disease. The data on the remaining B vitamins and chronic diseases are too meager to permit any conclusions.
Directions for Research
· The role of vitamin C in cancer needs to be defined. In particular, there is a need to identify the mechanisms other than nitrosamine inhibition whereby vitamin C may influence tumorigenesis. It is difficult to identify with certainty the effects due specifically to vitamin C because foods containing that vitamin also contain such potentially protective factors as fiber, carotenoids, and vitamin E.
· The requirements for water-soluble vitamins at all stages of the life cycle need to be determined as they may relate to the prevention of chronic disease, especially cancer and liver disease.
· A better understanding of the interactions among various nutrients (e.g., fiber, vitamin C, lipotropes) in the prevention of cancer and liver disease is needed.
· Greater attention should be directed to epidemiologic studies to gather data on the relationship of the B vitamins to cancer.
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