Beta-Carotene

What Is It?

Beta-carotene belongs to a group of phytochemicals called carotenoids and a sub-group called carotenes$^{1}$. Foods containing beta-carotene are often easy to point out as they possess a vibrant red-orange pigment that is seen in many fruits and vegetables such as apricots, red peppers and carrots$^{2}$. Other less suspecting foods with beta-carotene include green leafy vegetables like spinach and kale, where the strong pigment is masked by chlorophyll$^{2}$. Plant carotenoids are the predominant dietary source of provitamin A, and beta-carotene is the most common provitamin A carotenoid in foods$^{3}$. Beta-carotene is cleaved by the intestinal enzyme β,β-carotene 15,15'-monooxygenase to form two molecules of vitamin A$^{4}$. Vitamin A is an essential micronutrient and therefore must be obtained from our diet in order to sustain many crucial physiological processes including certain immune functions, cell growth, and vision$^{2}$. Overall, beta-carotene is most commonly known for its provitamin A activity which includes antioxidant and immunological effects$^{1}$.

What Are Its Other Names?

Beta-carotene is also known as 1,3,3-trimethyl-2-[(1E,3E,5E,7E,9E,11E,13E,15E,17E)-3,7,12,16-tetramethyl-18-(2,6,6-trimethylcyclohexen-1-yl)octadeca-1,3,5,7,9,11,13,15,17-nonaenyl]cyclohexene, β,β-Carotene, β-Carotene, Food Orange 5, Provitamin A, beta Carotene, Betacarotene, and Solatene$^{5}$.

What Foods Have It?

Note: The above data was acquired from a paper published in Molecular Nutrition & Food Research$^{}$$^{6}$.

What Are Its Main Benefits?

The large number of in vitro studies analyzing beta-carotene suggest promising cancer prevention abilities related to its vitamin A activity. Various in vitro studies investigating the cellular role of beta-carotene have found that it modulates carcinogenesis, particularly in the early stages, through antioxidant functions, immunomodulatory effects, and control of intracellular signalling$^{7,8}$. Additionally, beta-carotene has been shown to elicit more significant anticancer effects in combination with other compounds such as various carotenoids, vitamin E, vitamin C, and glutathione$^{7}$. Higher blood concentrations of beta-carotene and other carotenoids from fruits and vegetables have been associated with a lower risk of several chronic diseases such as cardiovascular disease, macular degeneration, and some cancers$^{9}$. Another benefit of beta-carotene when acquired through consumption of fruits and vegetables (and not supplements) is that it has not been shown to have toxic effects, thus making long-term administration for therapeutic purposes possible$^{7}$. Despite promising effects in cancer prevention and possibly treatment, much more research, particularly human clinical trials, is still required to elucidate the effects of beta-carotene on cancer risk and its impact on certain types of cancers.

What Are Its Main Drawbacks?

All populations

It should be noted that although beta-carotene is cleaved to form vitamin A in the body, consuming high amounts of beta-carotene from fruits and vegetables does not have the same negative consequences as consuming large amounts of preformed vitamin A (e.g. supplement form)$^{3}$. The human body only transforms beta-carotene into the amount of vitamin A that the body requires and stores the rest in fat for later use$^{2}$. This is not the case for vitamin A supplements which, in high amounts, can cause serious side effects such as birth defects in pregnant women$^{16}$. Another potential drawback of beta-carotene is that consistent high doses (25000 IU) may interfere with alpha-tocopherol absorption and metabolism in colonic tissue, which means that Vitamin E effects may be diminished in the colon$^{18}$. Furthermore, in excess, beta-carotene can cause carotenemia (a condition caused by high levels of carotenes in the blood), which is essentially benign aside from causing yellow-orange discolouration of the skin$^{3}$. Lastly, beta-carotene may cause harmful interactions with certain medications such as Orlistat (a weight loss drug), Acitretin (used to treat psoriasis), Bexarotene (used to treat skin effects of T-cell lymphoma), Cholestyramine (used to treat hyperlipidemia) and Verteporfin (used to eliminate abnormal blood vessels in the eye)$^{3}$. The interactions result in either very low blood levels of vitamin A or dangerously high blood levels of vitamin A, both leading to negative outcomes$^{3}$. Very low levels of vitamin A can cause Xerophthalmia (an eye condition characterized by the inability to see in low light), a higher risk of respiratory diseases, and it can also cause anemia$^{3}$. Very high levels of vitamin A can cause severe headaches, blurred vision, nausea and muscle aches$^{3}$. Smokers

The most significant drawback of beta-carotene is the adverse effects discovered with its use in large randomized human clinical trials involving patients who were smokers$^{10}$. This was witnessed in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC study) which demonstrated a significantly higher occurrence of lung cancer and total mortality in cigarette-smoking men consuming beta-carotene supplements in comparison to those taking the placebo$^{11}$. This was also later supported by the Beta-Carotene and Retinol Efficacy Trial which had similar results and lead to the premature ending of the study because participants in the supplementation group were experiencing statistically significant higher incidences of lung cancer than the placebo group$^{12}$. The mechanism by which this may occur was explored by researchers who conducted metabolomic profiling of 200 male smokers from the ATBC study. They found that 17 metabolites changed with beta-carotene supplementation$^{13}$. Many of these changes consisted of an increase in xenobiotic metabolites (usually breakdown products of drugs), which suggests an increase in cytochrome P450 enzyme induction$^{13}$. The findings of this study support the hypothesis that beta-carotene interacts with various prescription and non-prescription medications (such as asthma medication like ophylline, and cardiovascular disease medications like propranolol, tizanidine and verapamil) to reduce their efficacy and this is what could have ultimately lead to the increase of adverse effects in the ATBC study$^{13}$. Another study reported that in addition to lung cancers, the incidence of stomach cancers was also increased in smokers and asbestos workers supplemented with beta-carotene$^{14}$. Furthermore, a study investigating the effect of alpha-tocopherol and beta-carotene on radiation therapy for head and neck cancer in smokers found that the use of beta-carotene may reduce the efficacy of radiation therapy when combined with smoking$^{15}$.

How Does It Work?

Research suggests that beta-carotene exerts various preventative effects predominantly carried out through its vitamin A activity. Many of these anticancer properties include: potent antioxidant effects, enhancement of immune function, inhibition of angiogenesis, induction of apoptosis, and reduction of metastasis$^{9,19}$. Various studies also suggest that the combined effects of beta-carotene with other carotenoids present in fruits and vegetables may have more potent effects than beta-carotene alone$^{20,21,22}$. Among the high number of human intervention trials that have been conducted, many appear to have non-significant results, however several studies have also produced beneficial effects, and it is these that warrant further research into the anticancer abilities of beta-carotene. One cancer type that beta-carotene appears to be showing fairly consistent beneficial effects in is the prevention of oral cancers$^{12,23}$. To optimize the beneficial function of beta-carotene, it should be noted that the highest concentrations of carotenoids are found in fully ripe fruits and heat treatment has the potential to increase its bioavailability$^{2}$.

What Are Its Mechanisms of Action?

The mechanism by which beta-carotene acts is not well-defined in literature, however an overview of the current potential mechanisms are detailed below:

1. Antioxidant and Anti-Inflammatory Activity: As previously discussed, beta-carotene is a precursor to vitamin A and this vitamin has antioxidant capabilities that have been highlighted in many randomized controlled trials$^{24-32}$. Overall, these trials show that beta-carotene has the potential to prevent DNA damage by minimizing oxidative stress. This can be done through mechanisms such as lowering lipid peroxides (which are free radicals that attack lipids), decreasing 8-OHdG (a reactive oxygen species) in lung tissue, reducing micronuclei frequency (a biomarker of chromosomal damage) in sputum (a combination of saliva and mucus in the respiratory system), and reducing reactive oxygen species in gastric epithelial adenocarcinomas$^{25-30}$. In addition to this, vitamin A has anti-inflammatory activity, which has been demonstrated by Jang et al. who found that beta-carotene reduced expression of several downstream targets of the NF-kB pathway including iNOS and COX-2, both of which mediate the inflammatory response$^{27}$. Inflammation is closely linked to tumour promotion, so down-regulation of this pathway may be key to cancer prevention$^{32}$.
2. Enhances Immune Responses to Potential Tumours: The immunological effects of beta-carotene appear to be particularly promising as many of the randomized controlled trials investigating immune responses have generated beneficial effects. Firstly, beta-carotene supplementation may enhance tumor surveillance by increasing monocyte tumour necrosis factor (TNF)-alpha production$^{33,34}$. TNF-alpha is a crucial part of the inflammatory response and it leads to cell necrosis (rupturing of the cellular membrane causing cell death), which is particularly important in preventing tumour formation$^{35}$. Furthermore, beta-carotene supplementation may increase interleukin-2 signaling which influences regulatory and cytotoxic T lymphocytes (a specialized type of immune cell)$^{36}$. This increase in activated T lymphocytes will facilitate cytotoxic reactions on cancer cells via cytokines (secreted proteins used for cell signalling), ultimately causing cell death$^{36}$. Lastly, findings from another study show that long-term supplementation with beta-carotene enhances natural killer cell (important innate immune cells) activity in elderly men which may be beneficial for viral and tumoral surveillance$^{37}$.
3. Prevents Angiogenesis: Angiogenesis is defined as the development of new blood vessels, and this process allows for cancer metastasis$^{38}$. A study conducted by Mondul et al. found that supplementation with beta-carotene and alpha-tocopherol reduced serum concentrations of vascular endothelial growth factor-D, which is a growth factor involved in angiogenesis$^{39}$. Therefore, this is a potential mechanism for cancer prevention because if tumours do not have access to this vascular endothelial growth factor-D, they may not be able to develop new blood vessels to grow and spread throughout the body, ultimately inhibiting cancer progression$^{39}$.
4. Carotenoid Synergy: Although the focus of this article has been on beta-carotene supplementation alone, many studies have administered beta-carotene in addition to various other nutrients in what some call an ‘antioxidant cocktail’. It could be the synergistic effect of these antioxidants which include many carotenoids (e.g. beta-carotene, lycopene, lutein, etc.) that produce anticancer effects$^{40}$. Testing the use of this cocktail also better reflects how beta-carotene consumed through one’s natural diet (such as by eating fruits and vegetables) would act in the body. After analyzing a large number of randomized controlled trials, many that used 3 or more nutrients in addition to beta-carotene demonstrated efficacy in decreasing cancer incidence, with the majority being studies for prostate and colorectal cancers$^{20,21,22}$.

What Are Typical Doses and Durations?

The human clinical trials conducted using beta-carotene supplementation as a treatment, either on its own or in addition to other nutrients, have reported that beta-carotene is generally well-tolerated amongst participants (except for smokers). Although smokers experienced adverse effects to beta-carotene consumption, all other groups of participants have not reported tolerance issues$^{11}$. Among 90 randomized controlled trials, the dose of beta-carotene supplementation ranges from 10 mg – 60 mg per day, with the most common dose being 20 mg per day (refer to RCT Table). The duration of these studies ranges from 1 month to 12 years (refer to RCT Table). Although more research must be conducted to determine the optimal dose of beta-carotene, it is clear that a range of doses and durations of treatment are generally well-tolerated.

Summary of Data

Summary of randomized controlled trials administering beta-carotene alone or as an adjuvant to cancer therapy. A total of 29 studies that fit this criterion were found using the PubMed database.

Summary of randomized controlled trials administering various combinations of beta-carotene and 1 other supplement. A total of 11 studies that fit this criterion were found using the PubMed database.

Summary of randomized controlled trials administering various combinations of beta-carotene and 2 other supplements. A total of 12 (1 study was used twice because it discussed esophageal and gastric cancer) studies that fit this criterion were found using the PubMed database.

Summary of randomized controlled trials administering various combinations of beta-carotene plus 3 or more other supplements. A total of 8 studies that fit this criterion were found using the PubMed database.

Summary of association studies discussing circulating plasma levels of antioxidants and cancer incidence. A total of 4 studies that fit this criterion were found using the PubMed database.

Summary of randomized controlled trials and association studies administering beta-carotene alone or in addition to other supplements in populations of smokers. A total of 31 studies that fit this criterion were found using the PubMed database.

Below are links to detailed beta-carotene human clinical trial study notes analyzed by Anticancer.ca.

📄 Detailed beta-carotene (administered alone or as an adjuvant to cancer therapy) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed beta-carotene (+1 other supplement) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed beta-carotene (+2 other supplements) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed beta-carotene (+3 or more other supplements) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed "plasma levels of antioxidants and cancer incidence" association study notes analyzed by Anticancer.ca

📄 Detailed beta-carotene (administered to smokers alone or with other supplements) human clinical trial and association study notes analyzed by Anticancer.ca

References

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• Beta-Carotene
• What Is It?
• What Are Its Other Names?
• What Foods Have It?
• What Are Its Main Benefits?
• What Are Its Main Drawbacks?
• How Does It Work?
• What Are Its Mechanisms of Action?
• What Are Typical Doses and Durations?
• Summary of Data
• References
• About This Article
• Disclaimer