Inside Vitamin A
by Marc S. Micozzi, MD, Ph.D., Bethesda Maryland
Introduction
The medical world has been very vigilant about the possible toxicity of micronutrients. However, they remain reluctant to embrace the evidence that shows how optimal levels of micronutrients help prevent or treat diseases are higher than the well-established RDAs. Vitamin A is a particular example, where as a fat-soluble vitamin excess intake is not readily eliminated, leading to the possibility of toxicity. Today, while reports of hypervitaminosis A are rare, deficiency of vitamin A is common and can even be considered an epidemic in certain portions of the world’s population.
Vitamin A is very safe. National data from the American Association of Poison Control Centers repeatedly fails to show even one death from vitamin A per year. However, pregnancy is a special case where prolonged intake of too much preformed vitamin A might be harmful to the fetus, even at relatively low levels (under 20,000 IU/day). Interestingly enough, you can get over 100,000 IU of vitamin A from eating only seven ounces of beef liver. Have you ever seen a pregnancy overdose warning on a supermarket package of liver?
In fact, a lack of vitamin A, especially during pregnancy and in infancy, poses far greater risks. Deficiency of vitamin A in developing babies is known to cause birth defects, poor tooth enamel, a weakened immune system, and literally several hundred thousand cases of blindness per year worldwide. This is why developing countries safely give mega doses of vitamin A to newborns.
Vitamin A Metabolism
Vitamin A (retinol) functions as a constituent of visual pigments, supports normal reproductive capacity in both males and females, and supports normal cellular growth and differentiation. Among micronutrients, only retinol and its chemical derivatives can serve all of these biological functions. Recognition came in 1909, and naming in 1920, of the fat-soluble substance essential for normal growth we now call vitamin A. Preformed vitamin A, or the aldehyde and alcohol forms and their esters found mainly in animal products, including milk, eggs, meat, and fish is not synthesized by plants. However, provitamin A, which includes beta-carotene among several other carotenoids, is found in plant sources and cannot be synthesized either by humans or animals. Both forms are also commonly found in over-the-counter dietary supplements. For the most part, beta-carotene is converted to vitamin A during absorption through the intestinal mucosa, where both it and preformed vitamin A are transported in the plasma by lipoproteins. Vitamin A is then stored in fat cells of the liver.
Wolbach and Howe (1925) were the first investigators to discover a relation between vitamin A and cellular differentiation. It was discovered that dietary deficiencies in rats led to abnormalities in cellular differentiation. The restoration of vitamin A to their diet redifferentiated the cells.
Many subsequent studies, including that in 1941 by Abels et al. strongly supported the link between vitamin A and normal cellular differentiation. Recognition that vitamin A deficiency leads to abnormal growth of the skin spurred an initial rush to treat skin disorders with this new treatment. However, early excitement was tempered in light of toxic effects in many patients, especially on the liver.
Toxicity
A hominid or prehuman skeleton of Homo erectus (approx. 100,000 years ago) discovered in Kenya exhibited the earliest pathologically documented changes consistent with chronic excessive intake of vitamin A, or hypervitaminosis A. The clinical effects of excessive intake of vitamin A were first reported over 100 years ago, many years before vitamin A itself had even been positively identified. These reports involved the ingestion of polar bear and seal livers (5–8mg retinal/g liver) by Eskimos and Arctic explorers. Their acute symptoms included severe headaches, drowsiness, irritability, nausea, and vomiting. Twelve to 24 hours after ingestion, redness and loss of skin of the face, trunk, palms, and soles developed. Seven to 10 days later, all symptoms resolved.
Subsequent clinical observations verified major acute symptoms of
hypervitaminosis A - which occur when the intake of
vitamin A exceeds the
liver’s capacity to remove and store it - after ingesting a dose of at least
350,000 international units (IU) of
vitamin A by infants and 1,000,000 IU by
adults. Minor acute side effects are more frequent and better described; they
include dryness of skin and mucous membranes as well as ocular,
gastrointestinal, and musculoskeletal complaints such as tenderness of long
bones. Specific major chronic vitamin A toxicities include abnormalities of the
following: embryological development, reproductive function, serum lipids, liver
function, and the skeletal system. Minor chronic side effects resemble the minor
acute toxicities described above but are more subtle.
Micronutrient Interactions
The principal micronutrients shown to interact with
vitamin A
are
selenium,
zinc,
vitamin C,
vitamin E, and
iron.
Selenium is an effective
cancer-preventive agent in its own right, and its mechanism of action may be
similar to that of
vitamin A.
Several studies have indicated that interactions occur between zinc and vitamin A at many levels of cellular activity. Some human enzyme systems requiring zinc are directly and indirectly critical to vitamin A metabolism. Zinc reportedly influences the enzyme that catalyzes the conversion of retinaldehyde to retinoic acid. Indirectly, zinc may affect vitamin A through zinc-dependent enzymes, which may be involved in the synthesis of vitamin A carriers and cellular-binding proteins.
Research suggests that interactions occur between both vitamin C and vitamin E, with vitamin A. Some investigators believe that vitamin E has only a nonspecific, antioxidant role in its relationship with vitamin A. Vitamin E stabilizes cell membranes, while a deficiency shortens the survival time of red blood cells and accelerates the depletion rate of vitamin A stored in the liver. Vitamin E provides vitamin A and carotenoids with protection from oxidation in mixed diets. This protection results in higher levels of liver vitamin A and under certain circumstances, higher circulating vitamin A levels. Studies of vitamin E-deficient rats fed vitamin A indicate that vitamin E protects vitamin A at a cellular level as well. Vitamin E may also reduce vitamin A toxicity.
Vitamin A, deficiency and excess, appears to influence the liver’s synthesis of vitamin C (ascorbic acid) in animal models (humans cannot synthesize vitamin C). Vitamin C apparently acts as an antioxidant for vitamin A. Some reports claim to demonstrate a direct association between vitamin A deficiency and vitamin C synthesis.
High levels of iron in the intestine may contribute to destruction of vitamin A-active compounds. However, no data indicates that intake of high levels of inorganic iron causes vitamin A deficiency. Studies of human volunteers have revealed that vitamin A deficiency produces the gradual onset of anemia which responds to vitamin A, but not to medicinal iron supplementation. Nutrition surveys commonly reveal an association between anemia and inadequate dietary vitamin A.
Epidemiological studies of children in developing countries
showed a parallel increase in hemoglobin and serum
iron with increasing blood
levels of
vitamin A. Experimental studies of the interaction between
iron and
vitamin A show that iron absorption is not altered by vitamin A deficiency and
that
vitamin A appears to help mobilize stored
iron and incorporate it into red
blood cells.
Stem cells have been back in the news again. Vitamin A, in a test-tube experiment, will cause stem cells to change into cells that can build blood vessels. Vitamin A is known to be necessary for embryonic development precisely because it helps to ‘differentiate’ stem cells, pushing them to become normal tissue. There is an anti-cancer drug that specifically acts by blocking the breakdown of retinoic acid, derived from vitamin A, which allows vitamin A levels to build up. This approach has been found to be effective in treating animal models of human prostate cancer. Daily injections of the agent VN/14-1 resulted in up to a 50 percent decrease in tumor volume in mice implanted with human prostate cancer cells. No further tumor growth was seen during the five-week study. It seems that when cancerous tumors have more vitamin A available, they shrink. Keeping more retinoic acid available within cancer cells redirects these cells back into their normal growth patterns. This potent agent causes cancer cells to differentiate, forcing them to turn back to a non-cancerous state.
Vitamin A seems to induce positive, healthy, cell changes. Vitamin A derivatives are already in wide use to fight skin cancer. Another vitamin A derivative, 13-cis-retinoic acid, could protect against lung cancer development in former smokers. Significantly, the vitamin A derivative is used combined with alpha-tocopherol (vitamin E), in order to reduce toxicity known to be associated with 13-cis-RA (the vitamin A derivative) therapy. This point illustrates why nutritional physicians do not use high doses of vitamin A by itself, but rather give it in context with other important, synergistic nutrients. All nutrients are needed in a living body.
A study published in the Journal of Nutritional Biochemistry
found that administering both vitamin A and vitamin C to cultured human breast cancer cells was more than three times as effective than the administration of either compound alone. The combination of the two vitamins inhibited proliferation by over 75% when compared to untreated cells. The ability of retinoic acid (vitamin A) to inhibit tumor cell proliferation is well known, although its mechanism has not been defined. The authors suggest that the synergistic effect observed in this study is due to ascorbic acid’s ability to slow the degradation of retinoic acid, thereby increasing vitamin A’s cell proliferation inhibitory effects. Vitamin C helps vitamin A work even better.Both doctors’ experience and clinical evidence show that vitamin A helps prevent cancer which has been known for a long time. The association of vitamin A and cancer was initially reported in 1926 when rats, fed a vitamin A-deficient diet, developed gastric carcinomas. The first investigation showing a relationship between vitamin A and human cancer was performed in 1941 by Abels et al who found low plasma vitamin A levels in patients with gastrointestinal cancer. My colleague Tom Moon et al (Moon and Micozzi, 1989) reported daily supplemental doses of 25,000 IU of vitamin A prevented squamous cell carcinoma. And de Klerk and colleagues reported findings of significantly lower rates of mesothelioma among subjects assigned to retinol. Studies in animal models have shown that retinoids (including vitamin A) can act in the promotion-progression phase of carcinogenesis and block the development of invasive carcinoma at several epithelial sites, including the head, neck and lung. The Linus Pauling Institute states that studies in cell culture and animal models have documented the capacity for natural and synthetic retinoids to reduce carcinogenesis significantly in skin, breast, liver, colon, prostate, and other sites.
The NIH states that dietary intake studies suggest an association between diets rich in beta-carotene and vitamin A with a lower risk of many types of cancer. A higher intake of green and yellow vegetables or other food sources of beta carotene and/or vitamin A may decrease the risk of lung cancer. A study of over 82,000 people showed that high intakes of vitamin A reduce the risk of stomach cancer by one-half.
Conclusion
Vitamin A is alone among micronutrients in the ability to promote healthy cellular differentiation in addition to showing the beneficial anti-oxidant effects common to many vitamin and mineral micronutrients. For many Americans lost in the "alphabet soup" of dietary recommendations, healthy nutrition begins with Vitamin A. Since many Americans do not get the six to eight daily servings of fruits and vegetables that provide adequate micronutrient intake to promote good health, the solution for many Americans is high-quality supplementation.
References
Micozzi, MS, Complementary and Integrative Medicine in Cancer
Care and Prevention: Foundations and Evidence-Based Interventions, New York:
Springer, 2007. Moon, TE, Micozzi, MS, Nutrition and Cancer Prevention:
Investigating the Role of Micronutrients, New York: Marcel Dekker, 1989.
Drug Slows Prostate Tumor Growth by Keeping Vitamin A Active.
November 6, 2007. Findings from the AACR Centennial Conference on Translational
Cancer Medicine: From Technology to Treatment, Singapore, November 4-8, 2007 http://www.aacr.org/home/public--media/news/news-archives-2007.aspx?d=922
Annual Reports of the American Association of Poison Control
Centers’ National Poisoning and Exposure Database (formerly known as the Toxic
Exposure Surveillance System). AAPCC, 3201 New Mexico Avenue, Ste. 330,
Washington, DC 20016. Download any report from 1983-2006 at http://www.aapcc.org/dnn/NPDS/AnnualReports/tabid/125/Default.aspx
free of charge. The "Vitamin" category is usually near the end of the report.
Kim KN, Pie JE, Park JH, Park YH, Kim HW, Kim MK. Retinoic acid and ascorbic acid act synergistically in inhibiting human breast cancer cell proliferation. J Nutr Biochem. 2006 Jul;17(7):454-62. Epub 2005 Nov 15.
Basu S, Sengupta B, Paladhi PK. Single megadose vitamin A supplementation of Indian mothers and morbidity in breastfed young infants. Postgrad Med J. 2003 Jul;79(933):397-402. And: Rahmathullah L, Tielsch JM, Thulasiraj RD et al. Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomized trial in southern India. BMJ. 2003 Aug 2;327(7409):254.)
Larsson SC, Bergkvist L, Nlund I, Rutegd J, Wolk A. Vitamin A, retinol, and carotenoids and the risk of gastric cancer: a prospective cohort study. Am J Clin Nutr. 2007 Feb;85(2):497-503.
See Douglas Laboratories
® Product Reference Guide, 2009, Books and Reference Materials, p.13, Book 114.
Magnesium Stearate or Stearic Acid
Every few years the topic of magnesium stearate or stearic
acid and its putative toxicity arises. This topic is typically brought up by
companies trying to support their own particular philosophy of product
formulation, which does not include stearic acid. Over the years they have
promulgated a misleading story about the dangers of stearic acid and how bad it
is for you and for a product’s formulation. However, when one looks closely at
the data and studies that are often cited by those making these arguments, it is
clearly inaccurate to characterize stearic acid used in dietary supplements as
"dangerous". These "anti-stearic acid" arguments constitute a gross
mischaracterization of these studies and take much of the data completely out of
context. The argument is typically couched with sensational headlines, (such as
"poisonous flow agents") designed to get your attention and divert one from the
actual science with respect to stearic acid.
Stearic acid is an 18 carbon saturated fatty acid naturally found in many foods. The magnesium salt of stearic acid (magnesium stearate, also called vegetable stearate) is typically used in the formulation of dietary supplements. The material has a slippery consistency and is used as a flow agent to help raw material flow evenly and more easily into capsules. Stearic acid is allowed for use in dietary supplements and there is nothing inherently toxic or dangerous about stearic acid. However, when you read the one or two sentences that are often cited from the paper by Tebbey et al. (Immunology 1990), such as "Stearic acid inhibits T-cell dependent immune responses", it can sound scary. Nonetheless, when one reads the complete study it is clear that the authors were not studying dangers of stearic acid, or even making any connection between the consumption of stearic acid and any possible ill health effects. The study was actually looking in vitro (not in vivo) to see how B cells and T cells may metabolize compounds differently. The authors believed that these two cell types handled stearic acid differently and were performing experiments in an attempt to further understand the metabolism of these cell types. As it turns out, B cells had the ability to desaturate stearic acid, while T cells did not have that ability. The study was not performed to test the dangers of stearic acid and is not relevant to the quantities of stearic acid consumed from supplements (which is small) and was never tested in an in vivo system. These cells were directly exposed to stearic acid in a model system that does not reflect the in vivo situation.
In fact the authors were interested in the potential usefulness of stearic acid as it pertained to allograft rejection and autoimmune problems. To draw a connection between the results reported in the Tebbey et al. paper and a "danger" of stearic acid in supplements is simply bad science. Generalizing data from an unrelated in vitro study, which was never designed or intended to test the argument they are making, may make a nice marketing story; but that does not make it right.
A deeper look at stearic acid helps to further highlight the silliness of this argument and demonstrates the safety of the compound. Stearic acid is commonly found in many foods such as beef, cheese, milk, and coconut oil as well as foods that are considered to have interesting health benefits such as dark chocolate. The amount of stearic acid present in the foods we routinely consume is vastly greater than the few milligrams of stearic acid that are present in dietary supplement formulations. Additionally, once consumed, stearic acid is converted in the body to oleic acid, a monounsaturated fatty acid. This metabolic conversion may in fact be one of the reasons that stearic acid typically does not raise LDL cholesterol levels. This conversion of stearic acid to oleic acid in the body also makes it even harder to relate in vitro studies, that apply stearic acid onto cells, to any kind of in vivo situation.
Another example of taking results wildly out of context is an
often cited reference to a study by Ulloth, et. al.. In fact the full citation
is typically not given, but it appears to relate to an article that appeared in
the Journal of Neurochemistry in 2003. The authors were looking in vitro to see
if they could induce cell death with palmitic and stearic acid when given to
certain cells at concentrations similar to what is seen after traumatic brain
injury. Of course the "traumatic brain injury" aspect of the study is not
mentioned in the highlighted quote. How stearic acid, used in supplements, is at
all related to neuronal cellular metabolism following traumatic brain injury
remains a mystery. Nonetheless, taken out of context, it certainly sounds like
stearic acid may be bad for you. What it comes down to is this: stearic acid
used in supplements is safe and there have been no published data to demonstrate
otherwise. The often quoted references used to discredit steric acid sound
important and dangerous, but they are taken out of context. To use them to
support the argument that stearic acid should not be used in dietary supplements
misrepresents the data in the studies from which they were taken.
References
Tebbey PW, Buttke TM. Molecular Basis For
The Immunosuppressive Action of Stearic Acid on T cells. Immunology, 1990 70;
379-386
Ulloth JE, et al. Palmitic and stearic fatty acids induce caspase-dependent and -independent cell death in nerve growth factor differentiated PC12 cells. Journal of Neurochemistry 2003 84; 655-668
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