Beta-carotene (β-carotene ) forms and safety By Neil E. Levin, CCN, DANLA Amid the hype about “food grown” vitamins in general, and beta-carotene specifically, here is some science that may shed light on the issues. “Synthetic” beta-carotene comes in a form called “all-trans-beta-carotene”. However, since this form is found in nature, it is not really a “synthetic form” at all. In fact, about 50% of the carotenoids in algae sources of beta-carotene exist as the all-trans form, while beta-carotene from carrots has less than 14% cis-isomers and is about 86% trans-beta-carotene. Moreover, the all-trans form is much more efficient at raising body levels of vitamin A than the cis forms. This, plus its lower cost, smaller volume and better stability, make all-trans-beta-carotene the preferred form in many multiple vitamins. Here is a report stating that both cis and trans forms are found in a natural algae source: In the current study, we used a natural 9-cis retinoic acid precursor, 9-cis β-carotene, which is found in fruits and vegetables and in the highest levels in the alga Dunaliella bardawil. The alga accumulates high concentrations of β-carotene when grown under appropriate conditions. The β-carotene in the alga is composed of approximately 50% all-trans β-carotene and 50% 9-cis β-carotene isomers . The 9-cis β-carotene isomer has been shown to be a precursor of 9-cis retinoic acid both in vitro in human intestinal mucosa  and in vivo in a ferret perfused with 9-cis β-carotene . Hence, 9-cis β-carotene administration has the potential to improve fibrate action via its conversion to 9-cis retinoic acid. Shaish A, et al. 9-cis β-carotene-rich powder of the alga Dunaliella bardawil increases plasma HDL-cholesterol in fibrate-treated patients. Atherosclerosis. Volume 189, Issue 1, November 2006, Pages 215-221 Both forms are used by plants: Electroabsorption spectra of all-trans, 13-cis and 15-cis isomers of carotenoids violaxanthin and b-carotene frozen in organic solvents were analysed in terms of changes in permanent dipole moment, Dl, and in the linear polarizability, Da, on electronic excitation...For instance, the isomeric 15-cis form is usually present in the reaction centers as optimized for quenching of chlorophyll triplet states [1,2], while differently perturbed all-trans forms are optimized for non-radiative energy transfer in antenna systems . Krawczyk S, et al. Electroabsorption spectra of carotenoid isomers: Conformational modulation of polarizability vs. induced dipole moments. Chemical Physics 326 (2006) 465–470 trans-beta-carotene is the best form to provide vitamin A activity: Among the more than 600 carotenoids identified so far, only some 50 act as precursors of vitamin A, the presence of at least one unsubstituted b-ionone ring being the prerequisite for this important biological property. Because all-trans-b-carotene possesses two b-rings and may be cleaved into two molecules of retinal in the intestine by the enzyme b-carotene-15,150-dioxygenase, it has the highest provitamin A capacity. In contrast, considerably lower relative provitamin A activities of 53 and 38% are observed for 13-cis-b-carotene and 9-cis-b-carotene, respectively. Minguez-Mosquera,M. I., Hornero-Mendez, D., & Perez-Galvez, A. (2002). Carotenoids and provitamin A in functional foods. In W. J. Hurst (Ed.), Methods of analysis for functional foods and nutraceuticals (pp. 101–157). Boca Raton, London, New York, Washington, DC: CRC Press. Algal sources have different profiles of trans and cis carotenoids than other common sources, such as carrots: ..extracts of Dunaliella salina, which are known to contain relatively large amounts of b-carotene cis-isomers (Orset, Leach, Morais, & Young, 1999), are often used as a source of carotenes in supplements (Aman et al., 2004). In contrast, synthetic b-carotene is mainly applied in functional foods such as ATBC drinks, which contain provitamin A, vitamin C, and vitamin E as quality determining agents (Carle, 1999; Marx et al., 2000; Schieber et al., 2002). ATBC…drinks exclusively containing synthetic b-carotene were characterized by high relative amounts of cis-isomers (up to 44.5%), whereas those beverages containing carrot juice as a natural source of provitamin A showed significantly lower isomerization rates of up to 13.6% (Marx et al., 2000). These pronounced differences in the extent of isomerization have been explained by hot dissolution of synthetic microcrystalline all-trans-b-carotene and subsequent high-pressure homogenization, which are indispensable steps during manufacture of ATBC drinks (Carle, 1999). In continuation of these studies on carotenes in functional foods, commercial dietary supplements (soft gelatin capsule formulations, dragees, and effervescent tablets) have recently been investigated for their carotenoid stereoisomer profile. While both 9-cis- and 13-cis-b-carotene were detected in all samples assessed, no evidence for trans–cis-isomerization of lutein and zeaxanthin could be obtained (Aman et al., 2004). A. Schieber, R. Carle. Occurrence of carotenoid cis-isomers in food: Technological, analytical, and nutritional implications. Trends in Food Science & Technology 16 (2005) 416–422 The all-trans form is the most abundant in nature (which is the form found in many dietary supplements): Most naturally occurring carotenoids are in the all-trans-configuration; but under conditions of heating, for example, cis-isomers such as 13-cis-β-carotene (Figure 8-1) are formed. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000)Institute of Medicine (IOM) Of the many carotenoids in nature, several have provitamin A nutritional activity, but food composition data are available for only three (α-carotene, β-carotene, and β-cryptoxanthin) (Figure 4-1). The all-trans isomer is the most common and stable form of each carotenoid; however, many cis isomers also exist. http://books.nap.edu/openbook.php?record_id=10026&page=83 Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc (2000) Food and Nutrition Board (FNB) Institute of Medicine (IOM) beta-carotene supplements are more efficient at making vitamin A than food sources: Until recently it was thought that 3 μg of dietary β-carotene was equivalent to 1 μg of purified β-carotene in oil (NRC, 1989) due to a relative absorption efficiency of about 33 percent of β-carotene from food sources. Only one study has compared the relative absorption of β-carotene in oil versus its absorption in a principally mixed vegetable diet in healthy and nutritionally adequate individuals (Van het Hof et al., 1999). This study concluded that the relative absorption of β-carotene from the mixed vegetable diet compared to β-carotene in oil is only 14 percent, as assessed by the increase in plasma β-carotene concentration after dietary intervention. Based on this finding, approximately 7 μg of dietary β-carotene is equivalent to 1 μg of β-carotene in oil. This absorption efficiency value of 14 percent is supported by the relative ranges in β-carotene absorption reported by others using similar methods for mixed green leafy vegetables (4 percent) (de Pee et al., 1995), carrots (18 to 26 percent) (Micozzi et al., 1992; Torronen et al., 1996), broccoli (11 to 12 percent) (Micozzi et al., 1992), and spinach (5 percent) (Castenmiller et al., 1999) (Table 4-2). The matrix of foods affects the ability of carotenoids to be released from food and therefore affects intestinal absorption. The rise in serum β-carotene concentration was significantly less when individuals consumed β-carotene from carrots than when they received a similar amount of β-carotene supplement (Micozzi et al., 1992; Tang et al., 2000; Torronen et al., 1996). This observation was similar for broccoli (Micozzi et al., 1992) and mixed green leafy vegetables (de Pee et al., 1995; Tang et al., 2000) as compared with a β-carotene supplement. The food matrix effect on β-carotene bioavailability has been reviewed (Boileau et al., 1999). The extent of conversion of a highly bioavailable source of dietary β-carotene to vitamin A in humans has been shown to be between 60 and 75 percent, with an additional 15 percent of the β-carotene absorbed intact (Goodman et al., 1966). However, absorption of most carotenoids from foods is considerably lower and can be as low as 2 percent (Rodriguez and Irwin, 1972). Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000). Institute of Medicine. Vitamin A production is the primary function of carotenoids in humans. “…the only known function of carotenoids in humans is to act as a source of vitamin A in the diet… Lycopene, lutein, and zeaxanthin have no vitamin A activity and are thus referred to as nonprovitamin A carotenoids.” Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000) Institute of Medicine (IOM) The following table shows that dietary beta-carotene is about 1/6 as efficient at making vitamin A versus the form found in dietary supplements: Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc (2000) Food and Nutrition Board (FNB) Institute of Medicine (IOM) beta-carotene safety: Regarding beta-carotene safety, little has been resolved and the negative studies have been vigorously disputed. It has become apparent that blood levels of beta-carotene are not predictors of risk, but low levels of total antioxidants are. In fact, the dietary level of antioxidants is an independent predictor of plasma beta-carotene, especially in moderate alcohol drinkers. A recent study reports, “This may explain, at least in part, the inverse relationship observed between plasma beta-carotene and risk of chronic diseases associated to high levels of oxidative stress (i.e., diabetes and CVD), as well as the failure of beta-carotene supplements alone in reducing such risk.” Brighenti F. The total antioxidant capacity of the diet is an independent predictor of plasma beta-carotene. European Journal of Clinical Nutrition (2007) 61, 69–76. doi:10.1038/sj.ejcn.1602485; published online 12 July 2006. Supported by the European Community IST-2001–33204 'Healthy Market', the Italian Ministry of University and Research COFIN 2001 and the National Research Council CU01.00923.CT26 research projects. The National Institute of Medicine (NIH) has this to say about the safety of beta-carotene: What are the health risks of too many carotenoids? Provitamin A carotenoids such as beta-carotene are generally considered safe because they are not associated with specific adverse health effects. Their conversion to vitamin A decreases when body stores are full. A high intake of provitamin A carotenoids can turn the skin yellow, but this is not considered dangerous to health.Clinical trials that associated beta-carotene supplements with a greater incidence of lung cancer and death in current smokers raise concerns about the effects of beta-carotene supplements on long-term health; however, conflicting studies make it difficult to interpret the health risk. For example, the Physicians Health Study compared the effects of taking 50 mg beta-carotene every other day to a placebo in over 22,000 male physicians and found no adverse health effects . Also, a trial that tested the ability of four different nutrient combinations to help prevent the development of esophageal and gastric cancers in 30,000 men and women in China suggested that after five years those participants who took a combination of beta-carotene, selenium, and vitamin E had a 13% reduction in cancer deaths . In one lung cancer trial, men who consumed more than 11 grams/day of alcohol (approximately one drink per day) were more likely to show an adverse response to beta-carotene supplements , which may suggest a potential relationship between alcohol and beta-carotene.The IOM did not set ULs for carotene or other carotenoids. Instead, it concluded that beta-carotene supplements are not advisable for the general population. As stated earlier, however, they may be appropriate as a provitamin A source for the prevention of vitamin A deficiency in specific populations . 1. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. National Academy Press, Washington, DC, 2001. Here is my report on beta-carotene safety, as published in the peer-reviewed Journal of Applied Nutrition (Levin, N. Land of Confusion: How Poor Science and Misleading Media Coverage Create Public Confusion About How Dietary Supplements Affect Health. J App Nutr, Vol 55, No. 1, 2005 8-15) as recently updated with a newer study: Beta-carotene: Myth and Fact (Updated) The Myth: Beta-carotene causes cancer The Fact: Total antioxidants reduce cancer Some years ago an antioxidant study in Finland was halted early because of a widely reported increase in cancer rates among male smokers taking beta-carotene. 1 Headlines associated this supplement with cancer risk. Despite objections that the study was flawed, beta-carotene use dropped. A later analysis published in July 2004 took another look at that same Finnish smokers' study data, but now taking into account total antioxidant intake, which clears away the scientific controversy. The smokers’ risk of getting lung cancer was inversely associated with total antioxidants in the diet, with more total antioxidants meaning fewer cancers. 2 A composite antioxidant index was generated for each of the 27,000 men over 14 years. The calculated amounts of carotenoids, flavonoids, Vitamin E, selenium and Vitamin C were compared to actual lung cancer rates, with a clear result: the combination of antioxidants lowered lung cancer risk in male smokers. Another large study has noted that high carotenoid intake, confirmed by measures of blood levels, was associated with lower mortality rates among the elderly over a ten year period. 3 The dietary level of antioxidants is an independent predictor of plasma beta-carotene, especially in moderate alcohol drinkers. A more recent study reports, “This may explain, at least in part, the inverse relationship observed between plasma beta-carotene and risk of chronic diseases associated to high levels of oxidative stress (i.e., diabetes and CVD), as well as the failure of beta-carotene supplements alone in reducing such risk.” 4 Still, news reports continue to refer to beta-carotene as harmful, largely because of the original study reports. The “media myth” continues long after the science has moved on. REFERENCES: 1. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994 Apr 14;330(15):1029-35. http://content.nejm.org/cgi/content/full/330/15/1029?ijkey=bd47b716724d0dad4cad0fb19337308753658337 2. Wright ME, et al. Development of a Comprehensive Dietary Antioxidant Index and Application to Lung Cancer Risk in a Cohort of Male Smokers. July 2004 American Journal of Epidemiology http://aje.oupjournals.org/cgi/content/abstract/160/1/68?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&andorexacttitle=and&andorexacttitleabs=and&fulltext=beta+carotene&andorexactfulltext=and&searchid=1100534768534_1530&stored_search=&FIRSTINDEX=0&sortspec=relevance&fdate=7/1/2004&tdate=7/31/2004&journalcode=amjepid 3. Buijsse B, et al. Plasma carotene and alpha-tocopherol in relation to 10-y all-cause and cause-specific mortality in European elderly: The Survey in Europe on Nutrition and the Elderly, a Concerted Action (SENECA). Am J Clin Nutr 2005;82:879–886. 4. Brighenti F. The total antioxidant capacity of the diet is an independent predictor of plasma beta-carotene. European Journal of Clinical Nutrition (2007) 61, 69–76. doi:10.1038/sj.ejcn.1602485; published online 12 July 2006. Supported by the European Community IST-2001–33204 'Healthy Market', the Italian Ministry of University and Research COFIN 2001 and the National Research Council CU01.00923.CT26 research projects.