Maternal vitamin A supplementation in relation to selected birth defects

High doses of vitamin A cause birth defects in animals. Concern over vitamin A teratogenicity in humans has been prompted by reports of teratogenic effects of the vitamin A analogue, isotretinoin. The pattern of defects observed among isotretinoin- and vitamin A-exposed infants and animals suggests a possible mechanism involving cranial neural crest cell activity. Data from a case-control study were used to assess maternal use of vitamin A supplements alone and vitamin A-containing multivitamin supplements in relation to the occurrence of certain birth defects involving structures derived, at least in part, from cranial neural crest cells. Cases were 2,658 infants with such defects (primarily craniofacial and cardiac malformations). Controls were 2,609 infants with other malformations. Vitamin A supplementation was defined as daily use for at least 7 days of retinol alone or with vitamin D, or of fish oils. Information on vitamin A dose and nutrition was not available. The mothers of six controls used vitamin A supplements in each of the first three lunar months of pregnancy in comparison to the mothers of 15, 14, and 10 cases in lunar months 1, 2, and 3, respectively. Relative risk estimates and 95% confidence intervals were 2.5(1.0-6.2) for lunar month 1, 2.3(0.9-5.8) for lunar month 2, and 1.6(0.6-4.5) for lunar month 3. These findings should be considered tentative because no dose information was available, small numbers of cases and controls were exposed to vitamin A supplements, and relative risk estimates were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Retinoid-mediated regulation of mood: possible cellular mechanisms

Vitamin A and its derivatives, the retinoids, have long been studied for their ability to alter central nervous system (CNS) development. Increasingly, it is recognized that sufficient levels of retinoids may also be required for adult CNS function. However, excess dietary vitamin A, due to the consumption of supplements or foods rich in vitamin A, has been reported to induce psychosis. In addition, 13-cis-retinoic acid (13-cis-RA, isotretinoin), the active ingredient in the acne treatment Accutane, has been reported to cause adverse psychiatric events, including depression and suicidal ideation. Nevertheless, epidemiological studies have reported no consistent link between Accutane use and clinical depression in humans. Using an animal model, we have recently shown that 13-cis-RA induces an increase in depression-related behavior. Impairments in spatial learning and memory have also been demonstrated following 13-cis-RA treatment in mice. This review focuses on the behavioral and possible cellular effects of retinoid deficiency or excess in the adult brain in relation to altered mood. Specifically, we discuss the effect of retinoids on depression-related behaviors and whether norepinephrinergic, dopaminergic, or serotonergic neurotransmitter systems may be impaired. In addition, we consider the evidence that adult neurogenesis, a process implicated in the pathophysiology of depression, is reduced by retinoid signaling. We suggest that 13-cis-RA treatment may induce depression-related behaviors by decreasing adult neurogenesis and/or altering the expression of components of serotonergic neurotransmitter system, thereby leading to impaired serotonin signaling.     

Effects of excess vitamin A on development of cranial neural crest-derived structures: a neonatal and embryologic study

BACKGROUND: Vitamin A and its metabolites have been shown to be teratogenic in animals and humans producing defects of neural crest derived structures that include abnormalities of the craniofacial skeleton, heart, and thymus. Our prior studies with retinoic acid have established that gestational day (gd) 9 is a sensitive embryonic age in the mouse for inducing craniofacial and thymic defects. METHODS: We exposed pregnant mice to variable doses of vitamin A (retinyl acetate) on gd 9 and embryos were evaluated for changes in developing pharyngeal arch and pouch morphology, neural crest cell migration and marker gene expression. Additionally, we investigated whether a single organ system was more sensitive to low doses of vitamin A and could potentially be used as an indicator of vitamin A exposure during early gestation. RESULTS: High (100 mg/kg) and moderate (50 and 25 mg/kg) doses of vitamin A resulted in significant craniofacial, cardiac outflow tract and thymic abnormalities. Low doses of vitamin A (10 mg/kg) produced craniofacial and thymic abnormalities that were mild and of low penetrance. Exposed embryos showed morphologic changes in the 2nd and 3rd pharyngeal arches and pouches, changes in neural crest migration, abnormalities in cranial ganglia, and altered expression of Hoxa3. CONCLUSIONS: These animal studies, along with recent epidemiologic reports on human teratogenicity with vitamin A, raise concerns about the potential for induction of defects (perhaps subtle) in offspring of women ingesting even moderate to low amounts of supplemental vitamin A during the early gestational period.     

Teratogen update: vitamin A congeners

Despite animal vitamin A congener teratogenicity in animal studies since 1954, striking human findings only arose in 1983 following isotretinoin (ITR) marketing for oral treatment of severe acne. By November 1985, 44 outcomes with central nervous system (CNS), cardioaortic (CV), microtia, facial palsy, micrognathia, cleft palate, and/or thymic aplasia defects, and 33 spontaneous abortions have been reported. The critical period for exposure appears to be two to five weeks postconception, although this is clinically inexact. ITR half life is less than a day, although a teratogenic metabolite, 4-oxo-isoretinoin, has a half life of several days. Seven defect outcomes and one stillbirth have been reported with another congener, etretinate (ETR), used for psoriasis. Three of these had meningomyeloceles. Half life of several months makes levels cumulative. Only one additional defect, which may have occurred by chance, is reported with use stopped before conception (4 months). Other discontinuations 1 to 6 months before conception had 11 normal outcomes and two spontaneous abortions. ITR and ETR dose ranged from 0.5 to 1.5 mg/kg. Normal outcomes are reported both with ITR and ETR, but some of these appear not to have been exposed during the critical period. Less striking defects, abortions, and normal outcomes are less well reported. Because vitamin A analogs are therapeutically important and unplanned outcome not always avoidable, further animal research is needed for better risk/benefits. Megadose vitamin A (retinol) use is widespread, but experience poorly observed. Eighteen suspicious birth defect outcomes have been reported from pregnancies with high dose exposure. Twelve had findings similar to those seen in animals and in human retinoid syndromes, e.g., CNS, CV, microtia, and clefts. Epidemiological controls are lacking to establish human teratogenicity, but based on animal studies and experience with ITR and ETR, avoiding long term megadose Vitamin A use in fertile women is warranted.     

VitaminD supplementation for the prevention and treatment of COVID-19: a position statement from the Spanish Society of Geriatrics and Gerontology

The coronavirus disease 2019 (COVID-19) produces severe respiratory symptoms such as bilateral pneumonia associated to a high morbidity and mortality, especially in patients of advanced age. Vitamin D deficiency has been reported in several chronic conditions associated with increased inflammation and dysregulation of the immune system. Vitamin D in modulates immune function too. Vitamin D receptor (VDR) is expressed by most immune cells, including B and T lymphocytes, monocytes, macrophages, and dendritic cells and the signalling of vitamin D and VDR together has an anti-inflammatory effect. Some studies have reported that vitamin D treatment could be useful for the prevention and treatment of COVID-19 because vitamin D plays an important role as a modulator of immunocompetence. Over the last few months, some studies have hypothesized the possible beneficial effect of vitamin D supplementation in patients with COVID-19 in order to improve the immune balance and prevent the hyperinflammatory cytokine storm. Some preliminary studies have already shown promising results with vitamin D supplementation in hospitalized COVID-19 patients. Vitamin D should be administered daily until adequate levels are achieved due to vitamin D behaves as a negative acute phase reactant (APR). Despite the lack of evidence on specific doses of vitamin D to treat COVID-19 in older adults, authors consider it is necessary to standardize the use in clinical practice. These recommendations advice supplement vitamin D in a protocoled fashion based on expert opinions, level of evidence 5.     

Vitamin D: its role in cancer prevention and treatment

Vitamin D, the sunshine vitamin, has been recognized for almost 100 years as being essential for bone health. Vitamin D provides an adequate amount of calcium and phosphorus for the normal development and mineralization of a healthy skeleton. Vitamin D made in the skin or ingested in the diet, however, is biologically inactive and requires obligate hydroxylations first in the liver to 25-hydroxyvitamin D, and then in the kidney to 1,25-dihydroxyvitamin D. 25-Hydroxyvitamin D is the major circulating form of vitamin D that is the best indicator of vitamin D status. 1,25-dihydroxyvitamin D is the biologically active form of vitamin D. This lipid-soluble hormone interacts with its specific nuclear receptor in the intestine and bone to regulate calcium metabolism. It is now recognized that the vitamin D receptor is also present in most tissues and cells in the body. 1,25-dihydroxyvitamin D, by interacting with its receptor in non-calcemic tissues, is able to elicit a wide variety of biologic responses. 1,25-dihydroxyvitamin D regulates cellular growth and influences the modulation of the immune system. There is compelling epidemiologic observations that suggest that living at higher latitudes is associated with increased risk of many common deadly cancers. Both prospective and retrospective studies help support the concept that it is vitamin D deficiency that is the driving force for increased risk of common cancers in people living at higher latitudes. Most tissues and cells not only have a vitamin D receptor, but also have the ability to make 1,25-dihydroxyvitamin D. It has been suggested that increasing vitamin D intake or sun exposure increases circulating concentrations of 25-hydroxyvitamin D, which in turn, is metabolized to 1,25-dihydroxyvitamin D(3) in prostate, colon, breast, etc. The local cellular production of 1,25-dihydroxyvitamin D acts in an autocrine fashion to regulate cell growth and decrease the risk of the cells becoming malignant. Therefore, measurement of 25-hydroxyvitamin D is important not only to monitor vitamin D status for bone health, but also for cancer prevention.     

Vitamin D Metabolism and Guidelines for Vitamin D Supplementation

Vitamin D is essential for bone health and is known to be involved in immunomodulation and cell proliferation. Vitamin D status remains a significant health issue worldwide. However, there has been no clear consensus on vitamin D deficiency and its measurement in serum, and clinical practice of vitamin D deficiency treatment remains inconsistent. The major circulating metabolite of vitamin D, 25-hydroxyvitamin D (25(OH)D), is widely used as a biomarker of vitamin D status. Other metabolic pathways are recognised as important to vitamin D function and measurement of other metabolites may become important in the future. The utility of free 25(OH)D rather than total 25(OH)D needs further assessment. Data used to estimate the vitamin D intake required to achieve a serum 25(OH)D concentration were drawn from individual studies which reported dose-response data. The studies differ in their choice of subjects, dose of vitamin D, frequency of dosing regimen and methods used for the measurement of 25(OH)D concentration. Baseline 25(OH)D, body mass index, ethnicity, type of vitamin D (D₂ or D₃) and genetics affect the response of serum 25(OH)D to vitamin D supplementation. The diversity of opinions that exist on this topic are reflected in the guidelines. Government and scientific societies have published their recommendations for vitamin D intake which vary from 400–1000 IU/d (10–25 μg/d) for an average adult. It was not possible to establish a range of serum 25(OH)D concentrations associated with selected non-musculoskeletal health outcomes. To recommend treatment targets, future studies need to be on infants, children, pregnant and lactating women.     

Vitamin neurotoxicity

Vitamins contain reactive functional groups necessary to their established roles as coenzymes and reducing agents. Their reactive potential may produce injury if vitamin concentration, distribution, or metabolism is altered. However, identification of vitamin toxicity has been difficult. The only well-established human vitamin neurotoxic effects are those due to hypervitaminosis A (pseudotumor cerebri) and pyridoxine (sensory neuropathy). In each case, the neurological effects of vitamin deficiency and vitamin excess are similar. Closely related to the neurological symptoms of hypervitaminosis A are symptoms including headache, pseudotumor cerebri, and embryotoxic effects reported in patients given vitamin A analogs or retinoids. Most tissues contain retinoic acid (RA) and vitamin D receptors, members of a steroid receptor superfamily known to regulate development and gene expression. Vitamin D3 effects on central nervous system (CNS) gene expression are predictable, in addition to the indirect effects owing to its influence on calcium and phosphorus homeostasis. Folates and thiamine cause seizures and excitation when administered in high dosage directly into the brain or cerebrospinal fluid (CSF) of experimental animals but have rarely been reported to cause human neurotoxicity, although fatal reactions to i.v. thiamine are well known. Ascorbic acid influences CNS function after peripheral administration and influences brain cell differentiation and 2-deoxyglucose accumulation by cultured glial cells. Biotin influences gene expression in animals that are not vitamin-deficient and alters astrocyte glucose utilization. The multiple enzymes and binding proteins involved in regeneration of retinal vitamin A illustrate the complexity of vitamin processing in the body. Vitamin A toxicity is also a good general model of vitamin neurotoxicity, because it shows the importance of the ratio of vitamin and vitamin-binding proteins in producing vitamin toxicity and of CNS permeability barriers. Because vitamin A and analogs enter the CNS better than most vitamins, and because retinoids have many effects on enzyme activity and gene expression, Vitamin A neurotoxicity is more likely than that of most, perhaps all other vitamins. Megadose vitamin therapy may cause injury that is confused with disease symptoms. High vitamin intake is more hazardous to peripheral organs than to the nervous system, because CNS vitamin entry is restricted. Vitamin administration into the brain or CSF, recommended in certain disease states, is hazardous and best avoided. The lack of controlled trials prevents us from defining the lowest human neurotoxic dose of any vitamin. Large differences in individual susceptibility to vitamin neurotoxicity probably exist, and ordinary vitamin doses may harm occasional patients with genetic disorders.(ABSTRACT TRUNCATED AT 400 WORDS)     

Vitamin D compounds and diabetic nephropathy

Vitamin D therapies for renal disease have been used for over a half century and are likely to be utilized for many more years. Past roles have been to alter calcium and phosphorus metabolism to prevent or lessen bone disease and reduce PTH levels in dialysis patients and more recently, pre-dialysis patients. However, emerging evidence indicates new applications for vitamin D compounds are likely to exist for this patient population. In addition to the possible new targets in this therapeutic area, a popularly debated topic is the ideal form of vitamin D for use in renal disease. Because the vitamin D metabolism system is severely altered in kidney disease, a thorough understanding of the disease progression relative to the vitamin D signaling pathway is necessary. The current state of knowledge in this area with the primary focus on patients with diabetic nephropathy will be the scope of this review.     

Impaired glucose tolerance in vitamin D deficiency can be corrected by calcium

Vitamin D(3), via its active metabolite 1alpha,25-dihydroxyvitamin D(3), helps maintain normal calcium levels in the body. Apart from the maintenance of calcium homeostasis, the active form of vitamin D(3) is now known to be involved in a number of other functions including that of pancreatic beta cells. Low serum insulin levels and impaired glucose tolerance in a vitamin D-deficient state have been reported in experimental animals. Hypocalcemia is a major consequence of vitamin D deficiency. Whether the impairment observed is due to vitamin D deficiency per se or is secondary to low calcium is still a matter of controversy. The present study was conducted to delineate the roles of vitamin D and calcium in glucose intolerance associated with vitamin D deficiency in vivo. It was found that supplementation with either vitamin D(3) or high calcium alone to vitamin D-deficient rats could correct the defects. In addition, insulin sensitivity was found to be enhanced in the vitamin D-deficient group compared with vitamin D control or calcium-supplemented groups. Hence the present study demonstrates that calcium per se in the absence of vitamin D increases insulin secretion and normalizes intolerance to glucose seen in vitamin D deficiency.     

Effect of a high systemic background level of vitamin A on the teratogenicity of all-trans-retinoic acid given either acutely or subacutely

Groups of 12 Charles River CD virgin female rats were either supplemented with 25,000 IU/kg of vitamin A palmitate or not during the first 8 days of pregnancy and in the first experiment given a single dose of either 5 or 10 mg/kg of all-trans-retinoic acid (RA) on day 9 of pregnancy. In a second experiment, similar groups were given either 4 or 8 mg/kg RA daily from day 6 through day 15 so that each treatment with RA was given to vitamin A supplemented rats or nonsupplemented rats. The high systemic background of vitamin A increased the teratogenicity of the 10 mg/kg dose of RA given on day 9 by 50%, but reduced the teratogenicity of the 8 mg/kg dose given on days 6-15. The reasons for this paradox are discussed and related to the human propensity to self-medicate with megadoses of vitamins.     

More than metabolic: Considering the broader paleoepidemiological impact of vitamin D deficiency in bioarchaeology

Vitamin D deficiency has traditionally been viewed as a metabolic bone disease by bioarchaeologists and considered primarily in terms of the development of specific musculoskeletal changes used for diagnosis in paleopathological research. These skeletal manifestations are usually interpreted as representing general ill‐health. Clinical research shows that vitamin D is also integral to a number of extra‐skeletal physiological processes including immunoregulation, blood pressure homeostasis, cell division, and programmed cell death. Vitamin D deficiency and sub‐clinical insufficiency are thought to be risk factors for infectious and autoimmune diseases, as well as certain cancers and cardiovascular diseases. Epidemiological work indicates that the skeletal manifestations of vitamin D deficiency represent the extreme end of a spectrum of morbidity associated with negative health outcomes, including increased risk for secondary tuberculosis. This article provides a review of clinical research on the extra‐skeletal roles of vitamin D and the pathological consequences of poor vitamin D status. Additionally, it presents an interpretive model for bioarchaeological analyses of rickets and osteomalacia for consideration of the whole‐body impact of poor vitamin D nutriture and possible comorbidities that may have affected the wider population. Am J Phys Anthropol 160:183–196, 2016. © 2016 Wiley Periodicals, Inc.     

Antituberculous Therapy in Pregnancy: Risks to the Fetus

A total of 1,939 reported births to mothers who received isoniazid ethambutol, rifampin and streptomycin alone or in combination, for all or part of their pregnancies, were surveyed to determine teratogenicity of these agents. There was no significant increase in birth defects with isoniazid, ethambutol and rifampin, in contrast to the use of streptomycin which was associated with mild auditory and vestibular defects. Guidelines for the treatment of active tuberculosis in pregnancy are therefore established.     

A potential biotechnological process for the sustainable production of vitamin K1

The primary objective of this review is to propose an approach for the biosynthesis of phylloquinone (vitamin K₁) based upon its known sources, its role in photosynthesis and its biosynthetic pathway. The chemistry, health benefits, market, and industrial production of vitamin K are also summarized. Vitamin K compounds (K vitamers) are required for the normal function of at least 15 proteins involved in diverse physiological processes such as coagulation, tissue mineralization, inflammation, and neuroprotection. Vitamin K is essential for the prevention of Vitamin K Deficiency Bleeding (VKDB), especially in neonates. Increased vitamin K intake may also reduce the severity and/or risk of bone fracture, arterial calcification, inflammatory diseases, and cognitive decline. Consumers are increasingly favoring natural food and therapeutic products. However, the bulk of vitamin K products employed for both human and animal use are chemically synthesized. Biosynthesis of the menaquinones (vitamin K₂) has been extensively researched. However, published research on the biotechnological production of phylloquinone is restricted to a handful of available articles and patents. We have found that microalgae are more suitable than plant cell cultures for the biosynthesis of phylloquinone. Many algae are richer in vitamin K₁ than terrestrial plants, and algal cells are easier to manipulate. Vitamin K₁ can be efficiently recovered from the biomass using supercritical carbon dioxide extraction.     

The Association of Vitamin D Receptor Polymorphisms with Multiple Sclerosis in a Case-Control Study from Kuwait

Vitamin D deficiency is associated with several diseases including multiple sclerosis (MS). Several factors influence vitamin D levels and its optimal multi-function maintenance. Our objective was to assess quantifiable variables influencing vitamin D level and metabolism in MS patients from Kuwait. In a case-control study involving 50 MS patients, and 50 healthy control individuals for which plasma vitamin D levels, supplement use, vitamin D receptor (VDR) variants, and skin pigmentation indices were ascertained; we found overall vitamin D levels to be deficient in both groups, and supplement use to be common practice. VDR variants TaqI and BsmI associated with MS risk, and ApaI associated with low disease progression. VDR variant FokI associated with higher vitamin D levels in both groups. We conclude that several quantifiable variables related to vitamin D associate with MS suggesting a possible clinical immuno-modulatory application of vitamin D for MS patients in Kuwait.     

Vitamin E revisited: do new data validate benefits for chronic disease prevention?

PURPOSE OF REVIEW: Vitamin E benefits in human health and chronic disease prevention are evaluated with respect to established alpha-tocopherol functions during vitamin E deficiency, adequacy, and excess. RECENT FINDINGS: Baseline vitamin E status of the 29 092 Finnish men participating in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study showed that the men in the highest compared with the lowest quintile of serum alpha-tocopherol had significantly lower incidences of total and cause-specific mortality. New findings from the Women's Health Study support a role for vitamin E supplements in decreasing the risk for sudden death from cardiovascular disease and from thromboembolism. We speculate that a potential mechanism may involve vitamin E interference in vitamin K activation. SUMMARY: alpha-Tocopherol acts as a peroxyl and alkoxyl radical scavenger in lipid environments, and thus it prevents lipid peroxidation in lipoproteins and membranes, especially nervous tissues. Decreased chronic disease incidence is associated with lifelong generous dietary vitamin E intakes, but more than 90% of Americans do not consume the recommended dietary amounts (15 mg/day). Vitamin E supplements can have beneficial effects on health beyond those from dietary amounts, perhaps because pharmacologic levels also upregulate hepatic xenobiotic pathways.     

Chimeric analysis of retinoic acid receptor function during cardiac looping

Retinoids (vitamin A and its derivatives) play essential roles during vertebrate development. Vitamin A deprivation leads to severe congenital malformations affecting many tissues, including diverse neural crest cell populations and the heart. The vitamin A signal is transduced by the retinoic acid receptors (RARalpha, RARbeta, and RARgamma). However, these receptors exhibit considerable functional redundancy, as judged by the mild phenotype of RAR single null mutants relative to the defects evoked by loss of multiple RARs. To circumvent this redundancy, the endogenous RARgamma2 allele was replaced with a ligand-binding RARgamma mutant (RARgammaE(305)) by gene targeting in mouse embryonic stem (ES) cells. Chimeric embryos derived from hemizygous RARgammaE(305) ES cells displayed several defects similar to those observed in certain RAR double null mutants, including hypoplasia or absence of the caudal pharyngeal arches and myocardial deficiencies. The latter defects were not due to abnormal cardiac specification as affected hearts still expressed chamber-specific markers in an appropriate manner. Chimeras also displayed cardiac looping anomalies, which were associated with a reduction of Pitx2. This work suggests a role for RAR signaling in late looping morphogenesis and illustrates the utility of using a dominant-negative gene substitution approach to circumvent the functional redundancy inherent to the RAR family.     

Synthetic byproducts of tocopherol oxidation as inhibitors of platelet function

Vitamin E and its fully oxidized form tocopherol quinone are known inhibitors of platelet aggregation. Previous results from our laboratory have shown that the quinone was approximately equal in effectiveness to vitamin E. A recent report of a far greater inhibitory activity of the quinone produced by nitric acid oxidation of vitamin E prompted this investigation. Our studies show that the unusually high inhibition of platelet aggregation, release and cyclooxygenase activity associated with nitric acid oxidized vitamin E is due to byproducts of the oxidation process and not due to tocopherol quinone. Treatment of vitamin E acetate, a substance of mild effect on aggregation and arachidonate metabolism of platelets, with nitric acid did not produce tocopherol quinone but exerted as potent an inhibition as oxidized vitamin E. We conclude that nitric acid oxidation is unsuitable for preparation of tocopherol quinone unless the latter is carefully isolated. Oxidation with permanganate proved to be an alternate method without these difficulties.     

Update on the effects of vitamins A, C, and E and selenium on carcinogenesis

The effects of vitamins A, C, and E and of selenium on carcinogenesis are briefly summarized and updated. These vitamins and minerals were selected because they have been studied extensively in recent years with a variety of carcinogenesis models. The consumption of vitamin A and its precursors (carotenoids) has been negatively correlated with cancer at a number of sites, particularly the lung. Animal investigations on vitamin A involvement in carcinogenesis have generally been of three types: those assessing the effect of vitamin A deficiency, the effect of excess vitamin A, or the effect of supplementation with synthetic analogs of vitamin A. Vitamin A deficiency had no effect on salivary gland carcinogenesis, enhanced urinary bladder, lung, and liver carcinogenesis, and inhibited colon carcinogenesis. Excess of various forms of vitamin A enhanced or inhibited skin tumorigenesis, inhibited mammary carcinogenesis in rats (but not in mice), and carcinogenesis of the forestomach, liver, and urinary bladder (with one model, but not with another), or enhanced or did not influence lung carcinogenesis. Vitamin A analogs have enhanced or inhibited skin tumorigenesis, inhibited salivary gland, mammary, and urinary bladder carcinogenesis, enhanced tracheal and liver carcinogenesis, and either enhanced or inhibited pancreas carcinogenesis, depending upon the model employed. Although retinoids have been shown to inhibit carcinogenesis at many sites, numerous negative studies have been reported and some reports have indicated enhanced carcinogenesis. The most convincing evidence for the involvement of vitamin C in cancer prevention is the ability of ascorbic acid to prevent formation of nitrosamine and of other N-nitroso compounds. In addition vitamin C supplementation was shown to inhibit skin, nose, tracheal, lung, and kidney carcinogenesis, to either not influence or enhance skin, mammary gland, and colon carcinogenesis, and to enhance urinary bladder carcinogenesis, when given as sodium ascorbate, but not when given as ascorbic acid. Like vitamin C, vitamin E can inhibit nitrosation. Vitamin E was shown to inhibit skin, cheek pouch, and forestomach carcinogenesis, to enhance or inhibit colon carcinogenesis, and to have no effect on or to inhibit mammary gland carcinogenesis, depending upon the method of vitamin E administration or the level of dietary selenium or dietary fat. Selenium effects on carcinogenesis have been recently reviewed and the present discussion only updates this area by indicating that enhancement of carcinogenesis by dietary selenium supplements has been observed in the liver, pancreas, and skin.(ABSTRACT TRUNCATED AT 400 WORDS)