Home Journal Excerpts Cancer and Micronutrients DNA damage from micronutrient deficiencies is likely to be a major cause of cancer
DNA damage from micronutrient deficiencies is likely to be a major cause of cancer PDF Print E-mail
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Monday, 01 January 2001 00:00
“Approximately 40 micronutrients (the vitamins, essential minerals and other compounds required in small amounts for normal metabolism) are required in the human diet. For each micronutrient, metabolic harmony requires an optimal intake (i.e. to give maximum life span); deficiency distorts metabolism in numerous and complicated ways many of which may lead to DNA damage. The recommended dietary allowance (RDA) of a micronutrient is mainly based on information on acute effects, because the optimum amount for long term health is generally not known. For many micronutrients, a sizable percentage of the population is deficient relative to the current RDA. Remedying these deficiencies, which can be done at low cost, is likely to lead to a major improvement in health and an increase in longevity. The optimum intake of a micronutrient can vary with age and genetic constitution, state of well being, and be influenced by other aspects of diet. Determining these optima, and remedying deficiencies, and in some cases excesses, will be a major public health project for the coming decades. Long term health is also influenced by many other aspects of diet. Though this paper uses most examples from the US, the situation seems similar in many other countries.”

“Micronutrient deficiency can mimic radiation (or chemicals) in damaging DNA by causing single- and double-strand breaks, or oxidative lesions, or both. Chromosomal aberrations such as double strand breaks are a strong predictive factor for human cancer. Those micronutrients whose deficiency mimics radiation are folic acid, B12, B6, niacin, C, E, iron, and zinc, with the laboratory evidence ranging from likely to compelling. The percentage of the US population, for example, that is deficient (< 50% of the RDA) for each of these eight micronutrients ranges from 2 to > 20%, and may compromise in toto a considerable percentage of the US population. We have used < 50% of the US RDA as a measure of low intake because these numbers are available. However, the level of each micronutrient that minimizes DNA damage remains to be determined.”

“Micronutrient deficiency is a plausible explanation for the strong epidemiological evidence that shows an association between low consumption of fruits and vegetables and cancer at most sites.”

“Greater consumption of fruits and vegetables is associated with a lower risk of degenerative diseases including cancer, cardiovascular disease, cataracts, and brain dysfunction. More that 200 studies in the epidemiological literature have been reviewed and show, with great consistency, an association between low consumption of fruits and vegetables and the incidence of cancer. The quarter of the population with the lowest dietary intake of fruits and vegetables has roughly twice the cancer rate for most types of cancer (lung, larynx, oral cavity, esophagus, stomach, colon, rectum, bladder, pancreas, cervix, and ovary when compared to the quarter with the highest intake. In a different survey, the lowest quartile of adults consumed 2.7 portions or less and the highest quartile 5.6 portions or more (Krebs-Smith, personal communication). These observations are consistent with data on the Seventh Day Adventists, who are non-smokers and mostly vegetarian, and have about half the cancer mortality rate and a longer life span, than the average American. About 80% of American children and adolescents: and 58% of adults did not meet the intake recommended by the National Cancer Institute and the National Research Council: five servings of fruits and vegetables per day. Publicity about hundreds of minor hypothetical risks, such as that from pesticide residues in the diet, has contributed to a lack of perspective on disease prevention. Half of Americans do not list fruit and vegetable consumption as a protective factor against cancer and two-thirds think that for good health only two servings per day need to be consumed. Fruit and vegetable consumption is lowest among the poor, for example, African-American in the US.”

“Many components of fruits and vegetables may be responsible for their protective effect; such as micronutrients, plant phenolics, and fiber. This paper argues that inadequate intake of many micronutrients, such as folic acid, Vitamin C and B6 contributes to DNA damage, cancer, and degenerative diseases. A major part of the protective effect of fruits and vegetables may be due to their micronutrient content. In addition, dietary deficiencies of micronutrients whose sources are not primarily fruits and vegetables, such as zinc, iron, niacin, Vitamin E, and Vitamin B12, also appear to contribute to DNA damage and are also common in the US population. Other micronutrients are likely to be added to the list in the coming years.”

“Folic Acid

Folate deficiency, a common vitamin deficiency in people who eat few fruits and vegetables, causes chromosome breaks in human genes. Approximately, 10% of the US population are deficient a the level causing chromosome breaks in humans. In two small studies of low income (mainly African-American) elderly and adolescents done nearly 20 years ago about half had a folate deficiency at this level, though the issue should be re-examined. The mechanism of chromosome breaks has now been shown to be deficient in methylation of uracil into human DNA (4 million/cell). Uracil in DNA is excised by a repair glycosylase with the formation of a transient single-strand break in the DNA; two opposing single-strand breaks cause a double-strand chromosome break, which is difficult to repair. Both high DNA uracil levels and chromosome breaks in humans are reversed by folate administration. Folate supplementation about the RDA minimized chromosome breakage in an Australian study. Folate deficiency has been associated with increased risk of colon cancer, and the 15 year use of a multivitamin supplement containing folate lowered colon cancer risk by about 75%. Folate and B12 deficiencies are associated with cognitive defects in humans and neurotoxicity in children is caused by methotrexate, which lowers folate pools if folate is not replenished. Chromosome breaks could contribute to the increased risk of cancer, and possibly cognitive defects, associated with folate deficiency in humans. Folate deficiency causes increased homocysteine accumulation, which has been associated with neural tube defects in the fetus and an estimated 10% of US heart disease, both of which could be eliminated by folate supplements, food fortification, or better diets. Homocysteine damages endothelial cells in culture and is a risk factor for arterial endothelial dysfunction in humans.”

“Vitamin B12

The main dietary source of B12 is meat. About 4% of the US population consumes below half of the RDA of vitamin B12. About 14% of elderly Americans and about 24% of elderly Dutch have mild B12 deficiency, in part accountable by the Americans taking more vitamin supplements. Vitamin B12 would be expected to cause chromosome breaks by the same mechanism as folate deficiency. Both B12 and methyl-THF are required for the methylation of homocysteine to methionine. If either folate or B12 is deficient, the homocysteine, a major risk factor for heart disease, accumulates.”

“In a study of healthy Australian elderly men, or young adults, increased chromosome breakage was associated with either low intakes of folate, or B12, or with elevated levels of homocysteine. The B12 supplementation about the RDA was necessary to minimize chromosome breakage. The B12 deficiency is known to cause neuropathy due to demyelination and loss of peripheral neurons.”

“Vitamin B6

About 10% of the US population consumes less than half of the RDA (1.6 mg/day) of Vitamin B6. Vitamin B6 deficiency causes a decrease in the enzyme activity of serine hydroxymethyl transferase the only source of the methylene group of methylene-THF. If the methylene-THF pool is decreased in B6-deficiency, then uracil incorporation, with associated chromosome breaks, would be expected, and evidence for this has been found in women at a level of 32 nmol/l of Vitamin B6 in blood (0.5 mg/day intake) that were part of a pervious intervention study (Ingersoll et al., unpublished). In a case-control study of diet and cancer, Vitamin B6 intake was inversely associated with prostate cancer. Vitamin B6 deficiency appears to contribute to heart disease and supplementation reduces risk; levels above the RDA may be necessary to minimize risk. A level of Vitamin B6 in blood below 23 nmol/l is a risk factor for stroke and atherosclerosis. Diets low in Vitamin B6 are associated with brain dysfunction in children and adults. Good sources of Vitamin B6 are whole grain bread and cereal, liver, bananas and green beans. A major source in the US is fortified breakfast cereal and multivitamins.”

“Vitamin C

About 15% of the population consumes less than half the RDA (60 mg/day) of ascorbate which comes from dietary fruits and vegetables. The new RDAs for Vitamin C (90 mg/day for men, 75 mg/day for women and >35 mg for smokers) will make this percentage even higher.”

“There is a large literature on supplementation studies with Vitamin C in humans using biomarkers of oxidative damage to DNA, lipids (lipid oxidation releases mutagenic aldehydes), and protein. Though there are positive and negative studies, if the fact that the blood cell saturation occurs at about 100 mg/day is taken into consideration then the evidence suggests that this level minimizes DNA damage.”

“Cataracts appears to be due to oxidation of lens protein, and antioxidants, such as Vitamin C and E and carotenoids, appear to protect against cataracts and macular degeneration of the eye in rodents and humans. The use of Vitamin C supplements for 10 years so more reduced opacities by about 80%.”

“… increased oxidative damage from low Vitamin C intake, chronic inflammation, smoking, or radiation, together with elevated levels of uracil in DNA, would be expected to lead to more double-strand (chromosome) breaks in individuals who are deficient in both folate and antioxidants. There is some evidence for this synergy, which may be important because 10-15% of men in the US had serum ascorbate levels close to the scurvy threshold.”

“Some studies suggest that Vitamin C protects against cancer, which would be plausible based on the mechanistic data, though other studies show no effect, the variability of tissue saturation again is critical. A significant protective effect was observed for renal cancer in non-smokers, though not in smokers. In a review of nutrition and pancreatic cancer, fruit and vegetable intake and Vitamin C were protective, through it is difficult to rule out that Vitamin C is a surrogate for some other compounds in fruits and vegetables. Both experimental and epidemiological data suggest that Vitamin C protects against stomach cancer, a result that is plausible because of the role of oxidative damage from inflammation by Helicobacter pylori infection, which is the main risk factor for stomach cancer. The role of Vitamin C in inhibiting oral cancer has recently been reviewed. Vitamin C improves endothelial dysfunction, an early stage of atherosclerosis, in heavy smokers. Vitamin C supplementation was associated with a reduction in overall mortality and in cardiovascular disease in a follow up of the NHANES I study.”

“Men with low consumption of antioxidants, or who smoke, oxidize the DNA of their sperm as well as their somatic DNA. When the level of dietary Vitamin C is insufficient to maintain seminal fluid Vitamin C, the oxidative lesions in sperm DNA are more than doubled. Oxidative lesions in sperm DNA are higher in smokers than non-smokers. Smoking is a severe oxidative stress, and the nitrogen oxides (NOx) in cigarette smoke depletes antioxidants. Thus, smokers must ingest much more Vitamin C than non-smokers to achieve the same level in blood, but they rarely do. Inadequate Vitamin C levels are more common among the poor and smokers. Smokers also have more chromosomal abnormalities in their sperm than non-smokers.”

“Germ line mutations, and their associated cancer and genetic abnormalities, are predominately of paternal origin. Smoking by fathers, therefore, may plausibly increase the risk of childhood cancer and birth defects, a thesis supported by the epidemiological evidence. The evidence of smoking fathers' offspring having an increased rate of childhood cancer is becoming more persuasive. A new epidemiological study from China makes the case stronger; acute lymphocytic leukemia, lymphoma, and brain cancer are each increased three- to four-fold in offspring of male smokers. The studies on paternal smoking and childhood cancer did not examine the effect of diet. It seems likely, given the above evidence, that the cancer risk to offspring of male smokers would be higher when dietary antioxidant intake is low. Maternal use of multivitamins lower the risk of childhood cancer in offspring. In one study, the maternal use of vitamins throughout the pregnancy lower the risk of brain tumors in the offspring by about half. In a study of children with childhood cancer, serum levels of ß-carotene, Vitamin E, and zinc were significantly lower than in controls. Thus, a multivitamin supplement (or a better diet) for both parents might markedly lower childhood cancer. In addition, several studies suggest an increased rate of birth defects in offspring of smoking fathers.”

“Diets deficient in fruits and vegetables are commonly low in folate, antioxidants, (e.g. Vitamin C) and many other micronutrients, and it seems plausible that the higher cancer rates associated with consuming deficient diets are due, in good part, to increased DNA damage.”

“Vitamin E

Vitamin E, the major fat-soluble antioxidant, is consumed primarily from dietary vegetable oils and nuts. The RDA is 10 mg/day for men and 8 mg/day for women. About 20% of the population consumes less than half of the RDA. Evidence is accumulating that the optimum intake may be higher, as discussed below. Studies on Vitamin E supplementation have all been done with a-tocopherol, but g-tocopherol, the main form in the US diet, has a different function that a-tocopherol, and the two complement each other. g-Tocopherol is a powerful nucleophile, and thus, traps electrophilic mutagens that reach the membrane. In the soluble part of the cell, glutathione acts as both an antioxidant and nucleophile. In the membrane, a-tocopherol is the antioxidant and g-tocopherol (or lycopene) can act as a nucleophile. An important electrophilic mutagen destroyed by g-tocopherol is NOx. g-Tocopherol reacts with NOx to form nitro-g-tocopherol, thus, protecting lipids, DNA, and protein. g-Tocopherol is also an anti-inflammatory agent.”

“People taking Vitamin E supplements (200 IU/day) appear to lower their risk for colon cancer and evidence suggests a marked protective effect of a supplement (50 IU/day) of prostate cancer. Vitamin E appears to protect against brain dysfunction and deficiency leads to various neuropathologies.”

“Vitamin E supplements (100-400 IU), also reduced the risk of coronary heart disease by about 40% as well as mortality from all causes. The role of oxidants and the protective role of antioxidants in heart disease have recently been reviewed. Vitamin E is regenerated by Vitamin C. In a study of a population with low levels of Vitamin C and E, doses of Vitamin E from 70 to 560 IU lowered lipid peroxidation while a very high dose appeared to increase it emphasizing that information on the toxic level, as well as the optimum level, of each micronutrient is desirable.”

“Both Vitamin E and selenium enhance the immune system in animals, and Vitamin E supplementation (200-400 units/day) enhances human immunity. Vitamin E or Vitamin C reduced oxidative stress and malformations in offspring of diabetic rats.”

“Selenium

Selenium is important in enzymatic defenses against oxidants, and deficiency would be expected to lead to oxidative DNA damage. An RDA of 70 µg/day of selenium and upper limit of 350 µg/day has been proposed. The average intake in the US is about 100 µg/day, though different areas of the country have different selenium levels in the soil, and the bioavailability depends on the selenium form in foods.”

“A growing body of evidence suggests that selenium plays an important role in the prevention of cancer in a variety of organs and species. Prostate cancer incidence was reduced by two/thirds in the selenium supplemented group (200 µg/day) compared to the placebo group in a randomized, double-blind, cancer prevention trial; total cancer mortality, lung and colorectal cancer were also significantly reduced. In a cohort study, men in the highest selenium quintile of intake had only ½ the odds ratio of prostate cancer as men in the lowest quintile. In a nested, case-controlled prospective study on ovarian cancer, serum selenium was associated with decreased risk. In a study of post-menopausal breast cancer patients, a strong inverse relationship was observed between triiodothyronine (T3) levels and cancer (OR = 0.17; CI (95%) = 0.08-0.36) between the highest and lowest tertiles. Toenail selenium was positively associated with T3 levels in both cases and controls; the selenoenzyme iodothyronine diodinase synthesized T3. Prostate and breast cancer cells were about 25 times more sensitive than normal cells to selenomethionine, a major form of selenium in cells. In a study of selenium and colorectal cancer that adjusted for possible confounders, the individuals in the lowest quartile of plasma selenium had four times the risk of colorectal adenomas compared to those in the highest quartile. Selenium and glutathione peroxidase levels were found to be lowered in patients with uterine cervical carcinoma. In a Chinese study, cervical cancer mortality was inversely associated with several factors, including serum selenium levels. Selenoprotein-P level was inversely associated with several types of cancer. Selenium deficiency causes human cells in culture to be more sensitive to two mutagens causing single strand breaks in DNA.”

“Several hypotheses have been proposed to explain the protection against carcinogenesis by supplemental selenium. One of these is its protection against oxidative damage involving selenium as an essential component if the antioxidant enzyme glutathione peroxidase, or selenoprotein-P. A recent review discusses the 11 selenoproteins and selenium's role in preventing disease.”

“Excess selenium intake appears to cause oxidative damage and cancer in rodents. The case for selenium supplementation if becoming stronger, though the toxicity of high selenium levels must be taken into account.”

“Niacin

The main dietary sources of niacin include meat and beans. About 2.3% of the US population consumes less than half the RDA of niacin. Tryptophan from protein can also provide niacin equivalents. About 15% of some populations have been reported to be severely deficient. Niacin contributes to the repair of DNA-breaks by maintaining nicotinamide adenine dinucleotide levels for the poly-ADP ribose protective response to DNA damage; deficiency compromises repair of DNA nicks and breaks, and thus, is expected to act synergistically with folate and antioxidant deficiencies in causing DNA damage and cancer.”

“Iron

A major dietary source of iron is meat. The United Nations Food and Agriculture Organization has estimated that the world has about two billion people at risk of iron deficiency, mainly women and children. In the US, about 19%, aged 12-50, and about 7% of the population, ingest below 50% of the RDA; about nine million people have been estimated to be clinically deficient. Iron deficiency, or iron excess, leads to oxidative DNA damage. Iron deficiency in children is associated with cognitive dysfunction. Low iron intake results in anemia, immune dysfunction, and adverse pregnancy outcomes such as prematurity.”

“Excess iron appears to also lead to oxidative DNA damage in rats that is reversed by Vitamin E. Increased risk of human cancer and possibly heart disease is associated with excess iron.”

“Zinc

Major sources of zinc are meat, eggs, nuts, and whole grains. Zinc deficiency causes a variety of health effects which have been reviewed in depth. About 18% of the US population consumes less than half the RDA for zinc (12 mg women, 15 mg men). Mean daily intake reported for poor children (5 mg), middle income children (6.3 mg) and vegetarians (6.4 mg) in the US appear insufficient. Zinc is a component of over 300 proteins, over 100 DNA-binding proteins with zinc fingers, Cu/Zn superoxide dismutase, the estrogen receptor and synaptic transmission protein. Functioning of p53, a zinc protein which is mutated in half of human tumors, is disrupted on loss of zinc. Mutation is being prevented by p53, which inhibits cell division and induces apoptosis in response to DNA lesions.”

“Chromosome breaks in rats have been reported with a zinc deficiency. The offspring of zinc deficient rhesus monkeys also have increased chromosome breaks. The chromosome breaks might be due to increased oxidative damage, perhaps due to loss of activity of Cu/Zn superoxide dismutase or the zinc-containing DNA-repair enzyme, Fapy glycosylase, which repairs oxidized guanine. Zinc deficiency has been suggested as a contributor to esophageal cancer in humans, and has been shown to cause esophageal tumors in rats in conjunction with a single low dose of nitrosamine. Severe zinc deficiency by itself can cause esophageal tumors in rats.”

“Zinc is known to be an essential trace element for testicular development and spermatogenesis. Zinc concentrations in seminal plasma are hundreds of times greater than that in blood plasma, which suggests a specific function for this trace element in spermatogenesis and stability of spermatozoa. Zinc concentrations are correlated positively with sperm cell density, and lower zinc concentrations are found in infertile men compared with fertile men. Zinc deficiency leads to increased oxidative damage to testicular cell DNA (as measured by oxo8dG) and increased protein carbonyl content.”

“A considerable literature in experimental animals and humans suggest that zinc deficiency slows growth and development of the neonate. Severe deficiency in animals is teratogenic. In a pair-matched, double-blind, study in Chile of preschool boys of low socio-economic status, those supplemented with 10 mg zinc/day grew significantly more rapidly than the placebo group. This is consistent with earlier reports in the US and other countries on growth stimulation of poor children supplemented with zinc.”

“Zinc deficiency leads to alterations in brain development and growth. Zinc deficiency in pregnant rats, at a level that does not impair the pregnancy or the growth of the pups, impairs cognitive function in adult offspring. Zinc deficiency in adult rats impairs hippocampal and behavioral functions. Several studies on monkeys show that maternal zinc deficiency leads to learning and behavioral disabilities in offspring. Six studies in humans suggest that zinc deficiency leads to cognitive defects.”

“Several animal and human studies indicate that mild zinc deficiency impairs the immune system. The incidence of respiratory infections in a group of institutionalized elderly was decreased by over two-fold when they were given a supplement of zinc (20 mg) plus selenium (100 mg) in a double-blind placebo study; in other studies very high doses of zinc (100-150 mg/day) had an adverse effect on the immune system.”

“Conclusion

Optimizing micronutrient intake (through better diets, fortification of foods, or multivitamin-mineral pills) can have a major impact on public health at low cost. Other micronutrients are likely to be added to the list of those whose deficiency causes DNA damage in the coming years. Tuning-up human metabolism, which varies with genetic constitution and changes with age, is likely to be a major way to minimize DNA damage, improve health and prolong healthy lifespan.”


Ames, Bruce N., "DNA damage from micronutrient deficiencies is likely to be a major cause of cancer", Mutation Research, January 1, 2001, Vol. 475, Num. 0, pp. 7-20

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