This monograph reviews interactions issues relating to and deriving from intake of beta-carotene and other forms of provitamin A, as dietary components and supplements, and the metabolic processes of these substances within physiological/healthy, dysfunctional, and pathological processes and states. The related monograph for Vitamin A (Retinol) focuses on interactions issues involving intake, assimilation, and metabolic processes of the class of compounds that exhibit the biological activity of retinol. Inherently, interactions with some pharmaceutical agents involve both substances and their respective class of related substances.

Chemistry and Forms

Beta-carotene is the most well-known carotenoid, a class of related compounds found exclusively in plants (fruit and vegetable), where they are recognizable as brightly colored red, orange, and yellow pigments. Approximately 600 carotenoids have been identified, and about 50 are known to exert provitamin A activity; that is, they can serve as a naturally occurring precursor to vitamin A. Thus, “provitamin A” is the name of beta-carotene (and related compounds) that most directly describes its primary function in human physiology as viewed by conventional medicine. Alpha-carotene, lutein, lycopene, cryptoxanthin, and zeaxanthin are the most frequently occurring members of the group classified as “provitamin A carotenoids,” as is all- trans (i.e., synthetic) beta-carotene, which is actually the most active in terms of potential for conversion to vitamin A on a weight basis.

Beta-carotene consists of two retinol molecules. Bonds within beta-carotene are cleaved to form all- trans retinol (and possibly retinal , the aldehyde form of vitamin A); divergent theories exist regarding the site of this cleavage, the product(s) and their proportion, though molecular structures suggest that one molecule of beta-carotene would result in two molecules of retinol. It is not reasonable, however, to equate the predicted retinol yield of the various provitamin A carotenoids, then add these to provide units of “vitamin A equivalents,” because in non–vitamin A–deficient humans, only a small proportion of provitamin A carotenoids are actually converted to retinol or retinal. The supplement labeling convention of stating provitamin A carotenoid content in units of “retinol equivalents” has led to a widespread misperception among the lay public and many medical professionals alike, that such products contain potentially toxic levels of vitamin A. Potential toxicity of carotenoids, such as synthetic beta-carotene supplements in smokers, derives from the bimodal antioxidant/pro-oxidant phenomenon demonstrated by beta-carotene and is unrelated to issues of vitamin A toxicity.

Physiology and Function

In 1913, vitamin A was the first fat-soluble vitamin to be isolated. In 1929, Moore demonstrated that beta-carotene was converted into vitamin A, and 2 years later the chemical structures of both vitamin A and beta-carotene were determined. In 1932, beta-carotene (provitamin A) was discovered to be the precursor to vitamin A. Initially beta-carotene was considered to have the exclusive function in human physiology of serving as a source compound for conversion into vitamin A. The primary physiological functions of carotenoids include exerting antioxidant activity and deoxyribonucleic acid (DNA) protection, enabling both cell-mediated and humoral immunity, and feeding into the metabolic pathways of retinol, which is required for maintenance of all epithelial tissues.

The issue of bioavailability and conversion of beta-carotene and other provitamin A carotenoids to retinol remains contentious, evolving and often confusing because of uncertainty about the functional meaning of “bioavailability” and the inadequacy of the indicators used in its determination. Animal studies of the mechanism of carotenoid conversion to vitamin A indicate that before absorption, the two linked retinol molecules constituting beta-carotene can be converted to vitamin A in the wall of the small intestine. They are hydrolyzed in the gastrointestinal (GI) tract and absorbed into the mucosal cells of the small intestine, where they can be oxidized to retinoic acid and retinol in the presence of fat and bile acids. Carotenoids alpha, gamma, and beta are converted to vitamin A primarily in the intestinal mucosa. Theoretically, beta-carotene should be twice as active as the alpha and gamma carotenoids because it is composed of two potential molecules of retinol, and the others contain only one potential molecule of retinol. Both thyroxine and vitamin E enhance the conversion of carotene to retinol. Diabetes and hypothyroidism are two conditions that may impair conversion of carotenes to vitamin A. In non–vitamin A–deficient humans, it appears that the bulk of provitamin A carotenoids are absorbed intact and are not converted to vitamin A in significant quantities.

Absorption of beta-carotene and other carotenoids is influenced significantly by dietary intake, nutritional status, and storage levels, with efficiency of assimilation and utilization increasing in deficiency states and dropping with saturation of retinol and its metabolites. Beta-carotene and the other primary carotenoids with provitamin A activity demonstrate less bioavailability than retinol, also known as preformed vitamin A . Retinol itself is absorbed two to four times as efficiently as beta-carotene. Carotene relies much more on bile salts for absorption than retinol. Although retinol can also be absorbed from a micelle in the presence of any nonionic detergent, carotenoids can only be absorbed from a micelle in the presence of bile salts. Furthermore, carotenoids are absorbed by passive absorption regardless of their concentration, whereas retinol is absorbed by diffusion when present in high doses but is carrier mediated at low doses.

For all these reasons, only one third of ingested beta-carotene is absorbed, as much as 75% of which can be converted into retinyl esters and retinol, with 25% remaining intact as beta-carotene. Small amounts are then stored in the liver as active retinol. Beta-carotene is approximately one-sixth as biologically active as pure retinol. The resulting convention of 6 micrograms (µg) of beta-carotene being equivalent to 1 µg of retinol is generally accepted, but absorption, conversion, and utilization of carotenoids are highly variable. As the daily intake of carotene rises above 5000 international units (IU; on the basis of theoretical conversion to retinol), the percentage absorption rate decreases significantly. Ultimately, absorption is typically 20% to 50% but can be as low as 10% when intake is elevated.

Storage of beta-carotene and most carotenoids occurs primarily in adipose tissue, the adrenals, epidermal and dermal layers, and the corpus luteum, in contrast to vitamin A, which is predominantly stored in the liver. Minor amounts of beta-carotene are conjugated with glucuronic acid and converted to retinol in the liver; small amuts are also stored in the lungs. Colostrum also contains relatively high levels of carotenoids. Very-low-density lipoprotein (VLDL) or low-density lipoprotein (LDL) cholesterol transports intact beta-carotene in the blood, with blood levels varying according to intake levels. Serum levels of beta-carotene directly reflect daily consumption, not storage. Elimination of beta-carotene is primarily through the feces, but conjugated water-soluble forms are also excreted through the urine.

In plants the antioxidant effects of carotenoids enable these compounds to play a crucial role in protecting plant organisms against damage during photosynthesis. Beta-carotene functions as a chain-breaking antioxidant; rather than preventing initiation of lipid peroxidation, it stops the chain reaction by trapping free radicals, which halts the progression of free-radical activity. Many consider beta-carotene to be the most effective natural agent for quenching single-oxygen free radicals in humans. However, beta-carotene and other carotenoids exhibit a bimodal functionality characteristic of many “antioxidant” agents in that it can act either as an antioxidant or a pro-oxidant, depending on availability of other antioxidant compounds, and the level of oxidative stress present in the compartment in which it is acting.

The cis isomers of beta-carotene, which occur only in natural source, as opposed to synthetic all- trans beta-carotene, are the most potent scavengers of singlet-oxygen radicals. Under high-oxidative-stress conditions, such as in the lungs of smokers who have a poor dietary intake of other antioxidants, large quantities of beta-carotene, particularly of the all- trans isomer, can generate long-lived all- trans beta-carotene free radicals, which set in motion their own cell-damaging chain reactions, thus functioning as pro-oxidants rather than antioxidants. The presence of multiple antioxidant substances appearing together in their natural context emphasizes the interdependent network effect of diet-derived antioxidants and suggests that they provide optimal benefit when consumed together rather than as individual, isolated nutrients.

Both beta-carotene and retinyl esters from the diet are converted to retinal (11 cis isomer). Retinal is combined with the protein opsin to form rhodopsin in the rods of the retina and iodopsin in the cones. Light hitting the retina causes visual excitation and changes the cis configuration into the all- trans form of retinaldehyde. The rods are particularly sensitive to vitamin A deficiency. When retinol is in low supply, the all- trans form generated during the light reaction cannot be converted back to the active rhodopsin, which is why natural sources of carotenes and preformed vitamin A, which provide cis isomers, are needed in some cases to prevent or correct night blindness.

The roles and effects of retinol and the various metabolites of vitamin A are reviewed in the Vitamin A (Retinol) monograph and derive, at least in part, from the presence of beta-carotene and the other provitamin A carotenoids.

Known or Potential Therapeutic Uses

Until recently, conventional medicine has largely treated beta-carotene as simply a precursor of vitamin A (and assigned similar subsidiary roles to the other carotenoids). Over the past decade, beta-carotene and related carotenoids have been increasingly recognized as independent nutrients of physiological significance with parallel development of recommended intake levels. A small amount of beta-carotene is converted into vitamin A in the body, but beta-carotene and other carotenoids act independently from vitamin A as antioxidants as well as in other roles. Preliminary and experimental studies, as well as significant epidemiological data, suggest that a higher dietary intake of carotenes offers protection against developing certain malignancies (e.g., GI tract, lung, skin, cervix, uterus), macular degeneration, cataracts, and other health conditions linked to oxidative or free-radical damage.

Historical/Ethnomedicine Precedent

Some Western medical traditions, particularly naturopathic medicine, and many indigenous folk and professional traditions of plant medicine (i.e., food and herbs) have emphasized the importance of foods containing carotenoids, readily identifiable through their signature pigments, as important to supporting health and beneficial in treating disease. Mothers and grandmothers have long advocated the consumption of carrots, collards, spinach, and sweet potatoes as “good for you”; they may not have known the mechanisms involved, but they paid attention to outcomes. Modern research into the manifold benefits of the Mediterranean diet increasingly points to the significant contributions of colorful vegetables and fruits and healthy oils from olives and fish toward its salubrious effects.

Possible Uses

Alcohol withdrawal support, asthma, atherosclerosis, cancer (risk reduction), cataracts, cervical dysplasia, cognitive decline (protective; APOE 4 allele), coronary heart disease (risk reduction; in combination), gastritis, heart attack, human immunodeficiency virus (HIV) support, immune support, leukoplakia, lung cancer, macular degeneration, night blindness, osteoarthritis, photoprotection (erythropoietic protoporphyria), photosensitivity, pancreatic insufficiency, scleroderma, sickle cell anemia.

Deficiency Symptoms

Deficiencies of beta-carotene are associated with increased free-radical activity and a weakened immune system. However, comprehensive analysis of deficiency patterns is limited by a narrow conception of its physiological function and subsequent inadequacies in available research data. Scientific research into the deficiency patterns associated with compromised beta-carotene intake has largely been lacking, and specific symptoms attributable to deficiency have not been characterized. Much of the conventional medical literature has focused almost exclusively on beta-carotene's role as a dietary precursor of vitamin A, and as a result, framed deficiencies of this nutrient as largely synonymous with the symptoms of vitamin A deficiency. Inadequate dietary intake of fruits and vegetables rich in carotenoids, signaled by their bright orange, red, and yellow pigments, constitutes the primary cause of beta-carotene deficiency.

Dietary Sources

Beta-carotene occurs exclusively in plant foods (vegetables and fruits). Foods containing high amounts of beta-carotene are yellow and dark leafy green vegetables, especially carrots, collards, sweet potatoes, squash, spinach, and green, yellow, and red peppers, and yellow fruit such as apricot, cantaloupe, and peach.

Mild cooking of food sources (e.g., carrot) for short periods can significantly increase bioavailability compared with raw forms. However, beta-carotene is quite unstable, and exposure to oxygen reduces its potency. Frying, freezing, microwaving, and canning can reduce stable beta-carotene content of foods, whereas overcooking can significantly reduce bioavailability.

Continued uncertainty about the meaning of bioavailability of carotenoids, shortcomings in methods for determining bioavailability and absorption, and emerging knowledge of numerous factors in individual variability reveal fundamental inadequacies and inaccuracy in current systems for evaluating and comparing various forms of vitamin A, particularly those from dietary intake of carotenoid-containing foods. Given the wide range of reported conversion ratios of beta-carotene to vitamin A in humans, including the ratio of 6:1 for beta-carotene and 12:1 for alpha-carotene and cryptoxanthin devised by the World Health Organization (WHO), it appears prudent to consider all such approaches as, at best, providing only an estimate that is not applicable to all diets or individuals.

Dosage Forms Available

Capsule, liquid, tablet.

Source Materials for Nutrient Preparations

Naturally occurring beta-carotene contains 40% of the nutrient as the all -trans isomer and 38% in a form designated 9- cis . In contrast, synthetic beta-carotene is 97% “all- trans ” with virtually none of the “9- cis ” isomer. Absorption of 9- cis molecule from food sources may be less than the trans isomers, and it can be converted to all- trans beta-carotene quickly after assimilation, although actual in vivo fates of the various isomers are complex and uncertain.

Natural beta-carotene supplements can be derived from a variety of sources, such as the sea algae Dunaliella salina , and usually contains small amounts of other carotenoids, such as alpha-carotene, lycopene, and cryptoxanthins. However, most commercial products contain synthetic beta-carotene. Many supplements provide a combination of retinol and beta-carotene to increase carotenoid benefits and mitigate risks associated with vitamin A excess. Combinations of mixed carotenoids, along with other naturally occurring antioxidants, are favored by some health care professionals experienced in nutritional therapeutics.

Dosage Range

• Dietary:   2 to 6 mg/day.

• Supplemental/Maintenance:   No recommended dietary allowance (RDA) has been established for beta-carotene. The most common supplemental dose range of beta-carotene is 5000 to 25,000 IU (3-15 mg).

• Pharmacological/Therapeutic:   25,000 to 75,000 IU (15-45 mg).

• Toxic:   No toxic dose has been established.

One IU of beta-carotene is equivalent to one IU of vitamin A; 1 mg of beta-carotene is equivalent to 500 µg of vitamin A, although, as noted previously, these equivalencies are on a theoretical basis only.

1000 retinol equivalents (RE) = 1 mg retinol 6 mg beta-carotene 12 mg other provitamin A carotenoids 3330 international units (IU) vitamin A

Note: Further discussion of dosage issues and retinol equivalents is provided in the Vitamin A (Retinol) monograph.

Laboratory Values

Plasma beta-carotene: Normal: 0.3 to 0.6 mmol/L

Overview

In general, carotenoids are nontoxic, even when consumed in large amounts. Beta-carotene has a high safety profile, and documented reports of serious adverse effects are generally lacking. Absorption and assimilation are self-regulating, and beta-carotene is not stored to a significant degree. Conversion to retinol is tightly regulated.

Nutrient Adverse Effects

Supplemental intake of beta-carotene is not normally associated with adverse effects. However, excessive intake of beta-carotene or other carotenoids in very high amounts (>100,000IU, or 60 mg, per day) may result in hypercarotenemia and reversible yellow-orange discoloration of the skin. This can be distinguished from jaundice by the absence of scleral pigmentation.

Beta-carotene may have antagonistic effects on vitamin E status. Thus, it may be advisable to supplement vitamin E if large doses of beta-carotene are given for prolonged periods. In fact, it may be judicious to coadminister the entire range of fat-soluble nutrients to an individual who is taking large doses of beta-carotene for prolonged periods. ¹ There have been some reports of women who consume large amounts of carotenoids from foods becoming amenorrheic.

Hypercarotenemia can be associated with hypothyroidism, diabetes mellitus, liver/hepatic disease, and renal disease. It can also result from a rare genetic variation that reduces the ability to convert beta-carotene to vitamin A.

The most well-known, controversial, and misunderstood concern with potential adverse effects associated with beta-carotene intake derives from its bimodal relationship to oxidative stress. This paradoxical effect was highlighted in the Finnish Alpha Tocopherol Beta Carotene (ATBC) trial, conducted between 1985 and 1993. In this study, more than 29,000 middle-aged men in Finland, who smoked over a pack of cigarettes daily for an average of 36 years each, were divided into four groups and followed for 5 to 8 years. One group received 20 mg (or 33,000 units) of synthetic beta-carotene daily. A second group received 50 mg of synthetic vitamin E, in the form ofD,L-alpha tocopherol acetate. A third group received both these vitamins, and a fourth group received a placebo. The results of the study indicated a statistically significant 18% increase in incidence of lung cancer in the group receiving only beta-carotene, ² which may have been due to the beta-carotene functioning as a pro-oxidant under these conditions. Average consumption of fruits and vegetables in Finland is low, and average consumption of alcohol (another source of oxidative stress) is high. The soil (and thus food produced from it) is very low in selenium, an important antioxidant trace mineral that cofunctions with vitamin E.

In another large study, the U.S. Carotene and Retinol Efficacy Trial (CARET), investigators administered 30 mg of synthetic beta-carotene and 25,000 IU of vitamin A daily to half of a group of 18,000 participants, a fourth of whom were asbestos-exposed men, while the rest were either former or present smokers. The other half of the group received placebo. In this trial, the beta-carotene and vitamin A group had 28% more lung cancers and 17% more deaths than the placebo group. ³ That study was discontinued early because of this trend. Notably, there was no evidence of increased incidence of other forms of cancer related to beta-carotene administration. Beta-carotene may decrease levels of other carotenes, such as lycopene, lutein, and canthaxanthin, in the body. In smokers and people exposed to asbestos, these carotene levels may already be low. Some clinicians have suggested clinical trials with multiple carotenes as well as vitamin E and with vitamin E alone to differentiate the effects of these nutrients, which should prove beneficial; comparisons between supplements from natural sources versus those from synthetic sources and between food sources and supplements are also warranted. ⁴

In addition to the pro-oxidant effect associated with using high doses of synthetic beta-carotene in a population likely depleted of antioxidant reserves and under high oxidative stress, synthetic versus natural beta-carotene is also an issue. A 1989 Israeli study showed a 10-fold higher accumulation of natural beta-carotene versus synthetic beta-carotene in the livers of laboratory animals. The researchers stated, “Attention should be paid to the different sources of beta-carotene when testing their efficacy … such as in their possible role in the prevention of some types of cancer.” ⁵ Even more significantly, natural beta-carotene has shown the ability to rverse premdalignant gastric lesions, whereas synthetic beta-carotene had no activity of this sort. ⁶

General Adverse Effects

Hypercarotenemia caused by excessive intake is nonthreatening and reflects high concentrations of carotenoids in the plasma and characteristic tissues. The yellowish discoloration of the skin, often most noticeable on the palms and soles, and without yellowing of the whites of the eyes (in contrast to jaundice), is harmless and will gradually recede after excess intake has been halted.

Hypervitaminosis A is not associated with intake of beta-carotene or other carotenoids alone because efficiency of absorption decreases rapidly as intake dose rises, and because the relatively slow rate of conversion to vitamin A is usually inadequate to induce vitamin A accumulation and toxicity.

Diarrhea, dizziness, and arthralgia have been associated with high intake of carotenoid supplements on rare occasions. Reports of allergic reactions, amenorrhea, and leukopenia also appear in the literature, but their incidence appears to be rare.

Adverse Effects Among Specific Populations

Individuals with erythropoietic protoporphyria and related disorders may develop canthaxanthin retinopathy with extended intake of 50 to 100 mg of canthaxanthin, a relative of beta-carotene used therapeutically in such patients because it reduces the severe skin photosensitivity.

Hypercarotenemia can also result from a rare genetic variation that reduces the ability to convert beta-carotene to vitamin A.

Synthetic beta-carotene has been associated with increased risk of lung cancer in smokers. This pattern of risk also extends to those with high alcohol intake and increases further when both lifestyle stressors are combined. ^3,7,8

Pregnancy and Nursing

Beta-carotene is not known to increase the risk of birth defects. Animal studies indicate beta-carotene is not toxic to a fetus or a newborn; evidence of adverse effects from human trials or case reports is lacking.

Excretion in breast milk is unconfirmed but probable, given the fat-soluble nature of carotenoids. Caution and professional supervision may be appropriate with high-dose administration during lactation.

Infants and Children

No particular adverse effects or toxicity related to beta-carotene has been indicated for infants or children.

Contraindications

Smokers and other individuals with high oxidative stress, especially involving respiratory exposure, are strongly advised to avoid consumption of synthetic beta-carotene. Similar cautions may be appropriate for individuals with high alcohol intake. Ethanol can interact with beta-carotene and interfere with its conversion to retinol. Furthermore, ethanol can promote a deficiency of vitamin A while also increasing toxicity of both vitamin A and beta-carotene. Some evidence indicates that combining beta-carotene and ethanol may increase the risk of hepatotoxicity. ⁸ Moreover, in smokers who also consume alcohol, beta-carotene supplementation may further exacerbate oxidative stress to promote pulmonary cancer and, possibly, cardiovascular complications. This narrowed therapeutic window for beta-carotene (and retinol) needs to be considered when formulating treatments for vitamin A deficiency in populations with high ethanol consumption.

Caution may be appropriate in individuals with renal or hepatic impairment.

Although preformed vitamin A intake in excess of 1500 µg/day (5000 IU/day) has been associated with increased risk of osteoporotic fracture and decreased bone mineral density (BMD) in older men and women, no evidence or underlying pattern indicates that beta-carotene might induce such adverse effects on bone health.

Strategic Considerations

Interactions issues involving beta-carotene focus on three primary themes: antioxidant activity, decreased absorption and potential depletion, and purposeful coadministration. Patterns of clinical evidence are emerging in each of these areas, but scientific knowledge and clinical understanding are still limited, and further research is warranted through well-designed trials based on a clear understanding of the physiologic function of beta-carotene and related carotenoids and their roles in clinical practice.

Evidence suggests that mixed carotenes found in food can protect against cancer, cataracts, osteoarthritis, and heart disease. ^9-15Food rich in carotenoids (i.e., colorful vegetables and fruits) are generally considered more beneficial than isolated beta-carotene supplements. Furthermore, products containing only purified beta-carotene, especially of synthetic origin, may actually increase risk for or counter therapeutic measures against these conditions. ^2,7,16-19Thus, for physiological support, disease prevention, and therapeutic application, administration of a group of antioxidant nutrients, including carotenoids, is safer and more efficacious than administration of a single one, thus paralleling the natural pattern of diverse nutrient intake from nutritious food sources. Furthermore, although the body can convert beta-carotene into retinoids, the extent of that conversion is limited. Consequently, consumption of high doses of beta-carotene does not provide the same effect as intake of vitamin A itself.

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