Glass amber bottles containing synthetic, natural, and plant-based vitamins over background of supplement facts and anatomical figure.

Vitamins: Synthetic vs. “Natural” vs. Plant-Based​

Published:
May 9, 2015
Updated:
Oct 16, 2021

Disclosure: The information on this page has not been evaluated by the Food and Drug Administration (FDA). The information on this page is for educational purposes only and should be considered preliminary and/or inconclusive and not intended for the diagnosis, treatment, cure, or prevention of any disease. The information should not be considered as a claim for any particular food or dietary supplement. Always consult a medical professional for the diagnosis and/or treatment of a disease.

Table of Contents

Intro

This article will focus on provitamin A (carotenoids) and vitamin E (tocochromanols), and reveal the critical differences between synthetic, “natural”, and plant-based forms.

In this article, you will learn these 3 valuable lessons:

  • Which types of vitamins increase the risk of cancer, stroke, and heart disease: Learn why synthetic, or even so-called “natural” vitamin supplements, can be a threat to your health.
  • The critical importance of mixed vitamers: Learn how a broad-spectrum of vitamers is essential for health and which ones you need the most – carotenoids and tocotrienols.
  • Easy tips on interpreting the Supplement Facts panel: Learn how to spot the harmful vitamins in both food and supplements.

Provitamin A and vitamin E are not single substances but are in fact groups of vitamers. [1] Most conventional vitamin supplements only contain a single vitamer, while true plant-extracted supplements retain a broad-spectrum of vitamers. (Figure 1) Broad spectrum vitamers function as harmonious antioxidants, neutralizing the negative effects of free radicals. [2] [3] [4] [5] [6] However, once isolated from their natural relatives, single vitamers misbehave as hazardous pro-oxidants. [7] This article will examine the profound implications of this.

Figure 1. Most “natural” vitamin supplements are chemically stripped down to a single vitamer, which are more closely related to synthetic vitamins than true plant-based vitamins.

Before moving on, let’s review some important terms:

Vitamin Definitions
Vitamer:
A compound with biological and stuctural similarities to a particular vitamin. (e.g., alpha-tocopherol is a vitamer of the vitamin E family.) [1]
Vitamin A:
Includes retinoids with biological activity similar to retinol, also known as preformed vitamin A; includes carotenoids (e.g., beta-carotene) that convert to retinoids in the body, also known as provitamin A. [8] In the food supply, there are at least 6 carotenoids (vitamers) with provitamin A activity, and at least 50 other carotenoids with related or supportive functions. [9] [10] [11] (This article will focus on provitamin A and carotenoids.)
Vitamin E:
Includes tocochromanols that have biological activity similar to alpha-tocopherol. [8] In the vitamin E family, there are at least 13 known vitamers, including tocopherols and tocotrienols which are collectively referred to as tocochromanols. [12] [13]
Synthetic vitamin(s):
Created from industrial chemicals; consists of a single isolated vitamer.
Natural vitamin(s):
Term used by the supplement industry for vitamins that match the chemical structure of vitamins found in nature. However, most “natural vitamins” are more closely related to synthetic vitamins than plant-based vitamins due to chemical processing into a single isolated vitamer. [13]
Plant-based vitamin(s):
Extracted from fruits, vegetables, herbs, fungi, and other natural sources; retains the chemical structure and chemical diversity of vitamins and phytonutrients found in nature.
Antioxidant:
Any substance that delays, prevents or removes damage from free radicals, which may slow the progression of aging and disease. [2] Practically all vitamers play a role as an antioxidant, but not all antioxidants are vitamers. [2] [3] [4] [5] [6]
Definition of vitamin terms

The long-standing debate

For the past century, the belief that plant-based food can be replaced by a short list of chemicals has misguided researchers, physicians, and consumers alike. [14] [15] [16]

In 1962, researchers at the Stanford Research Institute attempted to match the natural composition of broccoli to create “synthetic broccoli” with 48 different ingredients including vitamins, minerals, amino acids, cellulose, glucose, and a small bit of vegetable oil. [17] Guinea pigs were fed the synthetic broccoli, and then subjected to gamma-radiation to mimic nuclear fallout. In the synthetic broccoli group, 95% of the guinea pigs died after the radiation exposure, while only 10% died in the group of animals fed real vegetables. [17]

As of 2015, at least 265,000 naturally occurring compounds have been identified and indexed. [18] Thousands of new compounds are added to this list each year. It is estimated that a single vegetable, such as broccoli, may contain over 10,000 unique substances, arranged in an infinitely complex matrix. [14] [19] Such a complex composition explains how 1 g of fresh apple, with only 0.057 mg of vitamin C, provides the same antioxidant protection as 15 mg of synthetic vitamin C. [20] Indeed, the superiority of plant-based vitamins comes from greater chemical diversity, not greater chemical quantity.

But if plant-based vitamins are so vastly superior, why have synthetic/isolated vitamins dominated our fortified foods and dietary supplements for the last 100 years?

To answer this question, let’s go back to the beginning of vitamin research.

A brief history of vitamins

In the 1930s, prior to the introduction of synthetic vitamins, research on vitamins was conducted using plant-based extracts. [15] Much of the early animal research on vitamin E utilized wheat germ oil, which contained not only a rich source of alpha-tocopherol, but also other E vitamers and phytonutrients. [21] In 1938, pure synthetic alpha-tocopherol became available to the research community. [1] Over the next several decades, researchers found that the synthetic vitamin E did not produce the same results as the crude plant-based extracts. [15] [21] [22] Some researchers believed that the “active” component had been missed entirely. [15] [21] Dr. Franklin Bicknell, a proponent for plant-based vitamins, believed that the failure of synthetics could be explained by the absence of the “complete complex” contained in the plant extracts. [22] Unfortunately, not all physicians and researchers acknowledged the unique functions and interdependencies among the different vitamers. [15] [21] [22]

Synthetic vitamins are made from industrial chemicals, while plant-based vitamins are extracted from fruits, vegetables, etc. However, In today’s market, most “natural” vitamin supplements are so extensively modified and purified they are essentially the same as synthetic vitamin supplements.

From the 1940s to the 1960s, much of the research on vitamin E focused on finding the most “active” form of vitamin E, so it could be studied independently. [15] The vitamin E family was ranked based on the ability to sustain reproduction in rodents. [23] Once established that alpha-tocopherol had the greatest activity in this bioassay, the other members of the vitamin E family (e.g., tocotrienols) were largely disregarded. [23] [24] [25] However, as we will learn in later sections of this article, each vitamer provides unique and symbiotic functions.

Although many early physicians and researchers recognized the superiority of plant-extracted vitamins (e.g., Catalyn®), those who advocated their use in patients were ridiculed by the FDA for prescribing crude, non-standardized treatments. [1] [14] [21] [22] [26] [27] [28] In addition, food-extracted vitamins suffered from batch-to-batch variability and a short shelf-life, which made scientific reproducibility difficult for researchers. [21] Eventually, synthetic vitamins became the preferred source due to their consistent potency and widespread availability. [1] [14] [21]

Failure in disease prevention

Throughout the 1980s, many large-scale studies found that populations with high blood levels of carotenoids and tocopherols had a lower risk of cancer, cardiovascular disease, and other chronic diseases. [29] [30] [31] Several test-tube and animal studies suggested that beta-carotene and alpha-tocopherol might be the active components for these long-term health benefits. [29] [32] [33] [34] [35] The optimism around supplemental vitamins was made clear when Tim Byers et al., with the Center of Disease Control (CDC), made the optimistic statement:

... cancer chemoprevention through supplementation and fortification of the diet with micronutrient antioxidants (vitamins) could become an effective strategy for cancer control before the close of this century.
Tim Byers
Centers for Disease Control (1992)

By the mid-90s, the first large human clinical trials were published on the effects of synthetic beta-carotene (20 mg/day) and alpha-tocopherol (50 mg/day) on lung cancer and other chronic diseases. (ATBC and CARET) [36] [37] Incidentally, the studies found that beta-carotene supplementation increased the risk of lung cancer and overall mortality, while alpha-tocopherol increased the risk of hemorrhagic stroke. [36] [37] Over the next decade, several more studies on alpha-tocopherol found an increased risk of prostate cancer and all-cause mortality. [38] [39] [40] [41] [42]

After two decades of damaging research, the faith in vitamin supplements for disease prevention started to disappear among the research community. In 2015, at the American Association for Cancer Research (AACR) Annual Meeting, Tim Byers retracted from his previous optimism:

We studied thousands of patients for ten years who were taking dietary supplements and placebos... We found that the supplements were actually not beneficial for their health. In fact, some people actually got more cancer while on the vitamins.
Tim Byers
Centers for Disease Control (2015)

Unfortunately, journalists, bloggers, and even Tim Byers himself have failed to clarify one key point. The harmful effects from “dietary supplements” and “vitamins” only been found from supplementation with synthetic and isolated vitamins. [7] [43] As we will learn, “dietary supplements” and “vitamins” cannot be categorically banished. The synthetic and isolated vitamin supplements administered in many publicized human clinical trials differ greatly from the vitamins extracted from fruits and vegetables – as do the health outcomes.

The following sections will highlight those differences.

Differences between synthetic, “natural”, and plant-based vitamins

If only single vitamer molecules were compared, we would find that synthetic, “natural”, and plant-based vitamers all share the same molecular structure. [16] [44] This, however, is where the similarity ends. Plant-based vitamin extracts include a diverse mixture of substances; including dozens of closely related vitamers and phytonutrients. (Figure 2) [45] [46] [47] [48]

Figure 2: Synthetic and even so-called “natural” vitamins contain single isolated vitamers, while plant-extracted vitamins contain dozens of vitamers and phytonutrients.

As you will see in the following sections, both synthetic and “natural” vitamin supplements consist of single isolated vitamers, and therefore have similar biological effects and health consequences. Because of this similarity, they can be collectively referred to as isolated vitamins, regardless of their synthetic or “natural” origins.

Composition

The compositional differences between synthetic/isolated and plant-based vitamins are compared side-by-side in the tables below.

Synthetic / Isolated
Provitamin A
Drums of chemicals as the origin of synthetic/isolated vitamins
Plant-Based
Provitamin A
Fruits and vegetables as the origin of plant-based carotenoids (provitamin A)
Common names:
beta-carotene, or all-trans-beta-carotene.
Common names:
mixed carotenoids, or beta-carotene from {plant name}.
Description:
Synthetic and even “natural” beta-carotene generally contain pure isolated beta-carotene (>98%) with no other vitamers or carotenoids. [16] This form of provitamin A is generally considered harmful.
Description:
Plant-based provitamin A retains a broad-spectrum of vitamers (carotenoids) and other phytonutrients. [48] This form of provitamin A is considered healthy and beneficial. An extract of palm fruit (African oil palm) is used as an example below.
Vitamers:
all-trans-beta-carotene
Vitamers:
9-cis-alpha-carotene
13-cis-alpha-carotene
all-trans-alpha-carotene
13-cis-beta-carotene
15-cis-beta-carotene
all-trans-beta-carotene
gamma-carotene
Other possible phytonutrients:
none.
Other possible phytonutrients:
d-alpha-tocotrienol
d-beta-tocotrienol
d-gamma-tocotrienol
d-delta-tocotrienol
d-alpha-tocopherol
d-beta-tocopherol
d-gamma-tocopherol
d-delta-
tocopherol
d-alpha-tocomonoenol
plastochromanol-8
9-cis-beta-carotene
delta-carotene
2-cis-zeta-carotene
lycopene
poly-cis-lycopene
phytoene
cis-phytofluene
neurosporene
alpha-zeacarotene
beta-zeacarotene
zeaxanthin
cryptoxanthin
squalane
coenzyme-Q10
coenzyme-Q9
beta-sitosterol
campesterol
stigmasterol
and others...
Table 1: Synthetic vs. plant-based provitamin A.

Many of the vitamin E products on the market claim to be natural. However, these products are chemically processed to convert all naturally occurring vitamers into pure alpha-tocopherol. [13] [44] There is no known source in nature that contains alpha-tocopherol without other E vitamers, therefore supplement companies selling isolated alpha-tocopherol as “Natural Vitamin E” are mislabeling their products and liable for a potential lawsuit. [49]

Synthetic / Isolated
Vitamin E
Drums of chemicals as the origin of synthetic/isolated vitamins
“Natural” / Isolated
Vitamin E
Fruits and vegetables as the origin of plant-based carotenoids (provitamin A)
Plant-Based
Vitamin E
Fruits and vegetables as the origin of plant-based carotenoids (provitamin A)
Common names:
dl-alpha-tocopherol, all-rac-alpha-tocopherol, or dl-alpha-tocopheryl esters (acetate, succinate, etc.)
Common names:
d-alpha-tocopherol, alpha-tocopherol, or RRR-alpha-tocopherol.
Common names:
mixed tocochromanols, mixed tocopherols and tocotrienols, or alpha-tocopherol from {plant name}.
Description:
Synthetic vitamin E contains a mixture of 8 different alpha-tocopherol isomers. [44] However, only the RRR-alpha-tocopherol exists in nature. Therefore, synthetic vitamin E is referred to as a single isolated vitamer. This form of vitamin E is generally considered harmful.
Description:
“Natural” vitamin E starts as an extract from soy or sunflower oil and undergoes chemical processing to convert the mixed vitamers into pure alpha-tocopherol. [13] [44] Although the alpha-tocopherol structure is identical to the “natural” form, this type of vitamin E is a single isolated vitamer. This form of vitamin E is generally considered harmful.
Description:
True plant-based vitamin E retains at least eight different E vitamers, and dozens of other phytonutrients. (50, 51) This form of vitamin E is considered healthy and beneficial. An extract of palm fruit (African oil palm) is used as an example below.
Vitamers:
RRR-alpha-tocopherol
RRS-alpha-tocopherol
RSR-alpha-tocopherol
RSS-alpha-tocopherol
SSS-alpha-tocopherol
SRS-alpha-tocopherol
SSR-alpha-tocopherol
SRR-alpha-tocopherol
Vitamers:
d-alpha-tocopherol
Vitamers:
d-alpha-tocotrienol
d-beta-tocotrienol
d-gamma-tocotrienol
d-delta-tocotrienol
d-alpha-tocopherol
d-beta-tocopherol
d-gamma-tocopherol
d-delta-tocopherol
d-alpha-tocomonoenol
plastochromanol-8
Other possible phytonutrients:
none.
Other possible phytonutrients:
none.
Other possible phytonutrients:
9-cis-alpha-carotene
13-cis-alpha-carotene
all-trans-alpha-carotene
9-cis-beta-carotene
13-cis-beta-carotene
15-cis-beta-carotene
all-trans-beta-carotene
gamma-carotene
delta-carotene
2-cis-zeta-carotene
lycopene
poly-cis-lycopene
phytoene
cis-phytofluene
neurosporene
alpha-zeacarotene
beta-zeacarotene
zeaxanthin
cryptoxanthin
squalane
coenzyme-Q10
coenzyme-Q9
beta-sitosterol
campesterol
stigmasterol
and others...
Table 2: Synthetic vs. “natural” vs. plant-based vitamin E.

The effect of these vitamins on health and disease will be discussed next.

Animal research

Provitamin A | isolated vs. broad-spectrum

Animal research has found that broad-spectrum carotenoids (palm fruit extract) are effective at preventing the formation of cancerous intestinal lesions in rats, while the single isolated vitamer beta-carotene is not. [52] Another study found that palm fruit based carotenoids can block UV (e.g. sunlight) related damage more effectively than isolated beta-carotene. [53] [54] One interesting study compared the liver protective effects of plant-based carotenoids and isolated beta-carotene. In this study, the mixed plant-based carotenoids provided greater protection against carbon tetrachloride liver poisoning. [55]

Vitamin E | isolated vs. broad-spectrum

In dogs, plant-based vitamin E (wheat germ oil extract) was compared to isolated alpha-tocopherol in the treatment of neurodegenerative disease. [21] It was found that the wheat germ oil extract reversed the neuromuscular symptoms in 84% of the dogs, while the alpha-tocopherol only improved the condition in 14% of the dogs. [21] Another study in dogs found that broad-spectrum vitamin E (palm fruit extract) protected brain cells against stroke-induced injury, while alpha-tocopherol alone was ineffective. [56] [57] Several studies have shown a protective effect of tocotrienols in rat brain cells against oxidative damage, while alpha-tocopherol alone failed to demonstrate a protective effect. [56] [57] [58] [59] [60]

In test-tube studies, broad-spectrum E vitamers from palm fruit extract have strong inhibitory effects on the growth of prostate cancer cells, while alpha-tocopherol alone has no effect. [61] [62] Similar results were found in human breast cancer cells, where mixed tocochromanols suppressed the growth of the cancer cells, whereas alpha-tocopherol alone had no effect. [63] [64] [65] Interestingly, the E vitamer gamma-tocopherol possesses anti-cancer activities, which are inhibited by excessive alpha-tocopherol. [66] This suggests that different E vitamers not only have synergistic effects, but may also act to counterbalance each other.

In the microscopic roundworm (C. elegans), palm fruit based tocochromanols provided protection against UV irradiation and prevented premature death, while isolated alpha-tocopherol provided no protection. [67]

Human research

Doctor checking blood work and blood pressure from patient

Provitamin A | isolated vs. broad-spectrum

Supplementation with synthetic beta-carotene has failed to protect against disease, and has instead produced a harmful effect in the majority of studies. [36] [37] [68] [69] [70] [71] [72] [73] Yet over 30 observational studies have shown that higher intakes of carotenoids from fruits, vegetables, and other plant foods are strongly associated with a lower risk of cardiovascular disease, cancer, and chronic disease. [12] [74] [75] [76] [77] [78] [79] [80] [81]

Vitamin E | isolated vs. broad-spectrum

Supplementation with isolated alpha-tocopherol has failed to show a benefit, and in several studies, has actually increased the risk of prostate cancer, cardiovascular disease, and death. [36] [38] [39] [40] [41] [42] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] In the major human clinical trials that have used “natural” (isolated) alpha-tocopherol (300-800 IU per day), only one study found a reduced risk of heart attack, two found no benefit, and one found a slightly increased risk of fatal heart attack. [40] [82] [90] [94] Thus, regardless of synthetic or natural origins, pure isolated alpha-tocopherol is generally ineffective or harmful. [36] [39] [40] [41] [42] [82] [83] [88] [89] [90] [91] [94]

On the other hand, there is a strong correlation between higher plant-based vitamin E intake and lower risk of cardiovascular disease and other chronic diseases. [31] [89] In addition, vitamin E supplementation from plant-based sources has never been associated with an increased risk of chronic disease, and instead, has been associated with beneficial and protective effects. [95] [96] [97] [98] [99] [100] [101] [102] [103]

Note: A side-by-side comparison of these studies can be found in the supplemental data sheet: Comparison of health outcomes by vitaminer type

Beneficial, harmful, or neutral?

Plotting the research findings shows consistent differences between isolated vitamers and broad-spectrum plant-based vitamers. The collection of human research shows that isolated vitamers have generally harmful effects, while broad-spectrum plant-based vitamers have generally beneficial effects. [7] [93] [104] (Figure 3)

Figure 3: Harmful effects are seen from single vitamers, while broad-spectrum mixed vitamers from plant-based vitamins show beneficial effects.

Therefore, the harmful effect from vitamins is a consequence of vitamin isolation. [35] [105] [106] When vitamins are retained with their naturally occurring mixture of vitamers, they maintain the valuable benefits associated with plant-based foods. [52] [53] [55] [95] [96] [97] [98] [99] [100] [101] [102] [103]

Why are synthetic/isolated vitamers harmful?

Research has demonstrated that isolated beta-carotene inflicts oxidative damage to DNA similar to smoking. [107] Accumulation of oxidative damage to the chromosome (e.g., DNA) is known to be a primary contributor to cancer. [108] In contrast, human studies have shown that plant-based carotenoids (which includes beta-carotene) can actually repair and reverse oxidative DNA damage, and is associated with a reduced risk of lung cancer. [109] [110] In addition, successful treatment of advanced stage lung cancer has been achieved with the Gerson Therapy, which includes the intake of 10+ glasses of fresh raw carrot juice per day. [111–113] This equates to about 220 mg (450,000 IU) of beta-carotene per day, which is 7 times greater than the dose used in the ATBC and CARET studies. [36] [37] [114] Thus, even massive amounts of beta-carotene are beneficial if taken with other naturally occurring carotenoids.

The increased risk of cardiovascular disease from isolated vitamin E (alpha-tocopherol) can be largely explained by the increased oxidative damage induced by alpha-tocopherol when given in its isolated form. [7] [115] [116] Cardiovascular disease is perpetuated by oxidative damage to LDL cholesterol. [117] [118] When LDL particles become oxidized, they are deposited within the artery wall and eventually transformed into a hard calcified plaque. [117] [118] When the plaque ruptures, it can cause a heart attack or stroke. [117]

Isolated vitamins are not harmful because of the dose, the population, or the pre-existing health conditions. Rather, isolated vitamins are problematic because they are isolated.

But how do isolated vitamers contribute to disease?

Isolated vitamers deplete other vitamers

In the food supply and conventional dietary supplements, beta-carotene or retinyl palmitate are used to boost the vitamin A value, while alpha-tocopherol is used to boost vitamin E value. This selective fortification with a single vitamer from these major vitamin groups creates nutritional gaps and imbalances. (Figure 4)

Figure 4: The relative dominance of the single vitamers which are commonly added to processed foods and vitamin supplements, highlighting deficiency in the other vitamers.

To make matters worse, supplementation with single vitamers can actually deplete related vitamers by ramping up the liver enzymes that accelerate the excretion of the entire family of vitamers. (Table 3) [119] [120] [121] [122]

Intake of isolated vitamer Effect on other vitamers
102 mg of isolated beta-carotene per day in adult men and women. Decreased serum lycopene by 50% after 3 weeks. [123]
30 mg of isolated beta-carotene per day in adult men. Decreased serum lutein by 38% after 6 weeks. [124]
30 mg of isolated beta-carotene in adult men. Decreased plasma alpha-tocopherol levels by 40% after 9 months. [125]
1000 mg of isolated alpha-tocopherol in adults. Decreased other tocopherols in plasma up to 40% after 8 weeks. [120]
Table 3: Synthetic/Isolated vitamins depleting other vitamers.

According to the CDC, only about 0.3% of the U.S. population is deficient in retinol, and less than 1% of the population is deficient in alpha-tocopherol, which technically fills the requirement for vitamin A and vitamin E, respectively. [126] [127] [128] However, for lesser known vitamers and phytonutrients, there are severe deficiencies in over 95% of the population. For example, the average intake of alpha-carotene is less than 0.4 mg/day, while research suggests 5 mg/day may be ideal for prevention of chronic disease. [126] [129] [130] [131] [132] [133] Similarly, the average daily intake of tocotrienols is less than 3 mg/day. [100] [101] [134] [135] [136] [137] [138] Yet, research suggests that the ideal intake is near 100 mg/day for brain and cardiovascular health. [25]

Thus, the modern day population is well covered on the “marker” vitamins which have established Recommended Dietary Allowances (RDAs) but is deficient in the relatively unrecognized carotenoids and tocotrienols.

Isolated vitamers increase oxidative damage

The provitamin A and vitamin E family are some of the most important fat soluble antioxidants obtained from the diet. [108] These antioxidants are stored in nearly all cells and tissues of the body, which neutralize free radicals to prevent oxidative damage to surrounding tissue. (Figure 5) [2]

Figure 5: The vitamer, beta-carotene, acting as an antioxidant by neutralizing a free radical.

As a part of normal functioning, a single cell in the body produces about 1,000 free radicals per second, and perhaps 100 times more than this in a state of oxidative stress when antioxidant defenses become overwhelmed. [2] Oxidative stress leads to oxidative damage inflicted upon lipids, proteins, and DNA. [2] As discussed in earlier sections, excessive oxidative damage contributes to cancer, cardiovascular disease, and other chronic diseases. [2] [108]

Free radicals must pass through a variety of biological compartments (e.g., mitochondria, cell membrane, etc) and travel across immiscible phases (e.g., oil and water) to be cleared from the body. [105] [139] [140] [141] [142] [143] [144] Tunneling free radicals through these various phases requires dozens of antioxidants (vitamers and phytonutrients) to work together in a closely integrated network. [5] [106] [139] [140] [141] [142] This antioxidant network forms the free radical transfer chain. (Figure 6) [139] [140] [141] [142]

Free radicals moving from one antioxidant to the next in a chain of eleven antioxidant molecules.
Figure 6: Dozens of antioxidants (e.g., vitamers) are required for the transfer and removal of free radicals.

As seen in Figure 6 and Figure 7, coenzyme-Q10, due to its long tail length, grabs free radicals deep within the cell membranes and passes free radicals to the next closest relatives; the carotenoids and tocochromanols. [141] [143] [144] [145] A greater variety of antioxidants broadens the “span” of the antioxidant network and helps remove free radicals more efficiently. [146] [147] Indeed, the protection from a single isolated antioxidant (vitamer) is extremely limited. [35] [106] [115] [139] [148] This was highlighted by a study that examined the effects of isolated beta-carotene in human subjects for 4 weeks. [149] The 120 mg/day dose did not provide any additional antioxidant protection than 15 mg/day, suggesting that the antioxidant network was limited by antioxidants other than beta-carotene. [149]

Antioxidants chained together removing free radicals through the cell membrane lipid bilayer.
Figure 7: Antioxidants working together to move free radicals through a cell membrane and into the plasma where they can be excreted and eliminated.

One study found that 100 mg/day of isolated beta-carotene for only 3 weeks actually increased oxidative damage in humans. [148]

But how can an antioxidant actually become a pro-oxidant?

For illustration, it’s helpful to compare the free radical transfer chain to a human bucket brigade that bails out trash from a factory. In a human bucket brigade, if ten buckets dumped into a single bucket, it would quickly overfill the single bucket. (Figure 8) Likewise, if people dropped buckets from the top of a 20 ft ladder, trash would spill everywhere. Thus, when an antioxidant significantly exceeds the capacity of neighboring antioxidants, or cannot effectively integrate with other antioxidants, it ultimately becomes a damaging pro-oxidant. (Figure 8) [5] [35] [115] [139] [141] [142] [148] [150]

Several molecules of beta-carotene overwhelming the antioxidant glutathione causing oxidative stress.
Figure 8: Isolated vitamers eventually dominate and overwhelm other vitamers; becoming damaging pro-oxidants which contribute to cancer and cardiovascular disease.

Naturally, as the variety of antioxidants increases, so does the antioxidant protection. [83] [105] [106] [115] One study found that cholesterol particles (e.g., LDL) are quickly damaged if coenzyme-Q10 becomes depleted, despite being saturated in alpha-tocopherol. [151] However, only one molecule of coenzyme-Q10 (i.e., CoQ-10) was required for every nine molecules of alpha-tocopherol to control oxidative damage. [106] [142] Thus, even trace levels of co-antioxidants (vitamers) can maintain antioxidant protection.

In summary, supplementation with isolated antioxidants (e.g., single vitamers) produces a disconnected, imbalanced, and unstable antioxidant network that increases the risk of cancer, cardiovascular disease, and other chronic diseases. [5] [7] [35] [115] [141] [142]

The Supplement Facts panel: distinguish harmful from healthy

On the Supplement Facts panel, synthetic and isolated vitamins are easily spotted by the listing of a single vitamin compound, especially when no plant or food source for the vitamin is listed. The compound may be found next to the vitamin line, or in the “other ingredients” section. (Figure 9)

Supplement Facts panel from synthetic vitamin supplement labels with highlighting of vitamin A and vitamin E as synthetic isolated vitamins.
Figure 9: Synthetic/isolated vitamins can be identified by looking for a single vitamer without any mention of its origin.

True plant-extracted vitamins can be identified by finding the listing of a specific plant source. For example; “Vitamin A (as beta-carotene from carrot extract)” would qualify as plant-based and would naturally contain a broad-spectrum of other carotenoids. (Figure 10)

Supplement Facts panel from a plant-extracted vitamin supplement labels with highlighting of vitamin A and vitamin E as broad-spectrum plant-based vitamins.
Figure 10: The plant source of the vitamin A and vitamin E in these products can be easily identified, indicating that these products contain a broad spectrum of vitamers.

Be warned, many vitamin supplements on the market, especially multivitamins, claim to be from “whole-foods” but a careful analysis of the Supplement Facts often reveals that these products contain synthetic/isolated vitamins in disguise.

How can companies get away with this?

If you see the yeast Saccharomyces cerevisiae (S. cerevisiae) or the bacteria Lactobacillus bulgaricus (L. Bulgaricus) on the Supplement Facts panel for a particular vitamin, this means that synthetic vitamins were incubated with these microbes in a fermentation process. [152] After the microbes are given a few days to absorb the vitamins, the material is dried, and pressed into tablets. Although these “cultured” vitamins may be more bioavailable than purely synthetic vitamins, they do not contain the same broad spectrum of vitamers found in plant-based vitamins.

Best practices for obtaining the health benefits from vitamins

For the greatest health and longevity, follow these best practices:

  1. Reduce intake of foods and supplements with synthetic / isolated vitamers: This will help prevent and reverse vitamer dominance caused by isolated vitamers.
  2. Consume fresh fruits, vegetables, herbs, coffee, and tea: This is important for obtaining a full spectrum of water-soluble and fat-soluble vitamers and phytonutrients. [19] [153]
  3. Consume plant-based supplements: Carotenoids and tocotrienols are lacking in over 95% of the U.S. population, even after consuming 2-3 servings of vegetables daily.  [129] [136] [154] Many B- and K-vitamins may also be difficult to obtain in sufficient quantity from common foods. [155] [156] Therefore, it is recommended to supplement with carotenoids, tocotrienols, and a plant-based multivitamin for full spectrum coverage.

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References

[1] COMBS, G., The Vitamins, Academic Press, Elsevier/ Academic Press (2012).

[2] HALLIWELL, B., GUTTERIDGE, J., Free Radicals in Biology and Medicine, Biosciences Oxford, OUP Oxford (2015).

[3] NATERA, J., MASSAD, W., GARCÍA, N.A., The role of vitamin B6 as an antioxidant in the presence of vitamin B2-photogenerated reactive oxygen species. A kinetic and mechanistic study, Photochem. Photobiol. Sci. 11 6 (2012) 938.

[4] VERVOORT, L.M., RONDEN, J.E., THIJSSEN, H.H., The potent antioxidant activity of the vitamin K cycle in microsomal lipid peroxidation, Biochem. Pharmacol. 54 8 (1997) 871.

[5] SIES, H., STAHL, W., Vitamins E and C, beta-carotene, and other carotenoids as antioxidants, Am. J. Clin. Nutr. 62 6 Suppl (1995) 1315S.

[6] WISEMAN, H., Vitamin D is a membrane antioxidant. Ability to inhibit iron-dependent lipid peroxidation in liposomes compared to cholesterol, ergosterol and tamoxifen and relevance to anticancer action, FEBS Lett. 326 1-3 (1993) 285.

[7] POLJSAK, B., MILISAV, I., The neglected significance of “antioxidative stress”, Oxid. Med. Cell. Longev. 2012 (2012) 480895.

[8] AIN COMMITTEE ON NOMENCLATURE, Nomenclature Policy: Generic descriptors and trivial names for vitamins and related compounds, The Journal of Nutrition 116 1 (1986) 8.

[9] DELA SEÑA, C. et al., Substrate Specificity of Purified Recombinant Human β-Carotene 15,15′-Oxygenase (BCO1), J. Biol. Chem. 288 52 (2013) 37094.

[10] BRITTON, G., LIAAEN-JENSEN, S., PFANDER, H., Carotenoids: Handbook, Birkhäuser Basel (2004).

[11] KHACHIK, F., BEECHER, G.R., GOLI, M.B., LUSBY, W.R., Separation and quantitation of carotenoids in foods, Methods Enzymol. 213 (1992) 347.

[12] FOOD AND NUTRITION BOARD, Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids, Dietary reference intakes, National Academies Press (2000).

[13] TAN, B., Appropriate spectrum vitamin E and new perspectives on desmethyl tocopherols and tocotrienols, Janasamkhya (2005).

[14] DECAVA, J.A., Natural Versus Synthetic Supplements, Whole Food Nutrition Journal (2003) 24.

[15] LEE, R., Vitamin News, Royal Lee library series, International Foundation for Nutrition & Health (2006).

[16] PATRICK, L., Beta-Carotene: The Controversy Continues, Alternative Medicine Review 5 6 (2000) 530.

[17] NEWELL, W., Further Studies of the Influence of Diet on Radiosensitivity of Guinea Pigs, with Special Reference to Broccoli and Alfalfa, Journal of Nutrition 79 3 (1963) 340.

[18] Dictionary of Natural Products, http://dnp.chemnetbase.com/intro/index.jsp.

[19] LIU, R.H., Health benefits of fruit and vegetables are from additive and synergistic combinations of phytochemicals, Am. J. Clin. Nutr. 78 3 Suppl (2003) 517S.

[20] EBERHARDT, M.V., LEE, C.Y., LIU, R.H., Antioxidant activity of fresh apples, Nature 405 6789 (2000) 903.

[21] LEVIN, E., Vitamin E vs. Wheat Germ Oil, The American Journal of Digestive Diseases 12 1 (1945) 20.

[22] BICKNELL, F., PRESCOTT, F., The Vitamins in Medicine, Grune & Stratton, New York (1953).

[23] BUNYAN, J., MCHALE, D., GREEN, J., MARCINKIEWICZ, S., Biological potencies of ε- and ζ1-tocopherol and 5-methyltocol, Br. J. Nutr. 15 02 (1961) 253.

[24] FOOD AND NUTRITION BOARD, Recommended Dietary Allowances: 7th Edition, National Research Council, National Academy of Sciences-National Research Council (1968).

[25] WONG, R.S.Y., RADHAKRISHNAN, A.K., Tocotrienol research: past into present, Nutr. Rev. 70 9 (2012) 483.

[26] JOLLIFFE, N., TREATMENT OF NEUROPSYCHIATRIC DISORDERS WITH VITAMINS, JAMA 117 18 (1941) 1496.

[27] SOPER, H.W., Clinical notes, The American Journal of Digestive Diseases 20 8 (1953) 227.

[28] LUTZ, K.B., PROTEST AGAINST PERSECUTION OF THE HEALTH MOVEMENT BY THE FOOD AND DRUG ADMINISTRATION, (1963).

[29] BYERS, T., PERRY, G., Dietary carotenes, vitamin C, and vitamin E as protective antioxidants in human cancers, Annu. Rev. Nutr. 12 (1992) 139.

[30] MAYNE, S.T., Beta-carotene, carotenoids, and disease prevention in humans, FASEB J. 10 7 (1996) 690.

[31] KNEKT, P. et al., Antioxidant vitamin intake and coronary mortality in a longitudinal population study, Am. J. Epidemiol. 139 12 (1994) 1180.

[32] STEINBRECHER, U.P., PARTHASARATHY, S., LEAKE, D.S., WITZTUM, J.L., STEINBERG, D., Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids, Proc. Natl. Acad. Sci. U. S. A. 81 12 (1984) 3883.

[33] BOSCOBOINIK, D., SZEWCZYK, A., HENSEY, C., AZZI, A., Inhibition of cell proliferation by alpha-tocopherol. Role of protein kinase C, J. Biol. Chem. 266 10 (1991) 6188.

[34] STEINER, M., ANASTASI, J., Vitamin E. An inhibitor of the platelet release reaction, J. Clin. Invest. 57 3 (1976) 732.

[35] KRINSKY, N.I., Actions of carotenoids in biological systems, Annu. Rev. Nutr. 13 (1993) 561.

[36] HEINONEN, O.P., ALBANES, D., The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and Other Cancers in Male Smokers, N. Engl. J. Med. 330 15 (1994) 1029.

[37] OMENN, G.S. et al., Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease, N. Engl. J. Med. 334 18 (1996) 1150.

[38] SLATORE, C.G., LITTMAN, A.J., AU, D.H., SATIA, J.A., WHITE, E., Long-term use of supplemental multivitamins, vitamin C, vitamin E, and folate does not reduce the risk of lung cancer, Am. J. Respir. Crit. Care Med. 177 5 (2008) 524.

[39] KLEIN, E.A. et al., Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT), JAMA 306 14 (2011) 1549.

[40] STEPHENS, N.G. et al., Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS), Lancet 347 9004 (1996) 781.

[41] LONN, E. et al., Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial, JAMA 293 11 (2005) 1338.

[42] SESSO, H.D. et al., Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial, JAMA 300 18 (2008) 2123.

[43] MARTÍNEZ, M.E., JACOBS, E.T., BARON, J.A., MARSHALL, J.R., BYERS, T., Dietary supplements and cancer prevention: balancing potential benefits against proven harms, J. Natl. Cancer Inst. 104 10 (2012) 732.

[44] JENSEN, S.K., LAURIDSEN, C., Alpha-tocopherol stereoisomers, Vitam. Horm. 76 (2007) 281.

[45] MARTINIS, J., KESSLER, F., GLAUSER, G., A novel method for prenylquinone profiling in plant tissues by ultra-high pressure liquid chromatography-mass spectrometry, Plant Methods 7 1 (2011) 23.

[46] NOWICKA, B., KRUK, J., Occurrence, biosynthesis and function of isoprenoid quinones, Biochim. Biophys. Acta 1797 9 (2010) 1587.

[47] MÈNE-SAFFRANÉ, L., JONES, A.D., DELLAPENNA, D., Plastochromanol-8 and tocopherols are essential lipid-soluble antioxidants during seed desiccation and quiescence in Arabidopsis, Proc. Natl. Acad. Sci. U. S. A. 107 41 (2010) 17815.

[48] PING, B.T.Y., MAY, C.Y., Practical Guide to Establishing Palm Carotenoids Profiles by HPLC with Three Dimensional Diode Array Detector, Palm Oil Developments 33 (2000) 13.

[49] CROMWELL, M., WEAVER, K., Litigation Risks and Exposures: “All Natural” Claims, (2013).

[50] HAN, N.M., MAY, C.Y., Chromatographic analyses of tocopherols and tocotrienols in palm oil, J. Chromatogr. Sci. 50 3 (2012) 283.

[51] TRUJILLO-QUIJANO, J., RODRIGUEZ-AMAYA, D.B., ESTEVES, W., PLONIS, G.F., Carotenoid Composition and Vitamin A Values of Oils from Four Brazilian Palm Fruits, Fett - Lipid 92 6 (1990) 222.

[52] NARISAWA, T. et al., Inhibitory effects of natural carotenoids, alpha-carotene, beta-carotene, lycopene and lutein, on colonic aberrant crypt foci formation in rats, Cancer Lett. 107 1 (1996) 137.

[53] SOMEYA, K., TOTSUKA, Y., MURAKOSHI, M., KITANO, H., MIYAZAWA, T., The effect of natural carotenoid (palm fruit carotene) intake on skin lipid peroxidation in hairless mice, J. Nutr. Sci. Vitaminol. 40 4 (1994) 303.

[54] SOMEYA, K., TOTSUKA, Y., MURAKOSHI, M., KITANO, H., MIYAZAWA, T., The antioxidant effect of palm fruit carotene on skin lipid peroxidation in guinea pigs as estimated by chemiluminescence-HPLC method, J. Nutr. Sci. Vitaminol. 40 4 (1994) 315.

[55] MURTHY, K.N.C., RAJESHA, J., SWAMY, M.M., RAVISHANKAR, G.A., Comparative evaluation of hepatoprotective activity of carotenoids of microalgae, J. Med. Food 8 4 (2005) 523.

[56] RINK, C. et al., Tocotrienol vitamin E protects against preclinical canine ischemic stroke by inducing arteriogenesis, J. Cereb. Blood Flow Metab. 31 11 (2011) 2218.

[57] KHANNA, S. et al., Neuroprotective properties of the natural vitamin E alpha-tocotrienol, Stroke 36 10 (2005) 2258.

[58] SEN, C.K., KHANNA, S., ROY, S., PACKER, L., Molecular basis of vitamin E action. Tocotrienol potently inhibits glutamate-induced pp60(c-Src) kinase activation and death of HT4 neuronal cells, J. Biol. Chem. 275 17 (2000) 13049.

[59] KAMAT, J.P., DEVASAGAYAM, T.P., Tocotrienols from palm oil as potent inhibitors of lipid peroxidation and protein oxidation in rat brain mitochondria, Neurosci. Lett. 195 3 (1995) 179.

[60] KHANNA, S. et al., Nanomolar vitamin E alpha-tocotrienol inhibits glutamate-induced activation of phospholipase A2 and causes neuroprotection, J. Neurochem. 112 5 (2010) 1249.

[61] NESARETNAM, K., KOON, T.H., SELVADURAY, K.R., BRUNO, R.S., HO, E., Modulation of cell growth and apoptosis response in human prostate cancer cells supplemented with tocotrienols, Eur. J. Lipid Sci. Technol. 110 1 (2008) 23.

[62] SRIVASTAVA, J.K., GUPTA, S., Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells, Biochem. Biophys. Res. Commun. 346 2 (2006) 447.

[63] NESARETNAM, K., DORASAMY, S., DARBRE, P.D., Tocotrienols inhibit growth of ZR-75-1 breast cancer cells, Int. J. Food Sci. Nutr. 51 Suppl (2000) S95.

[64] NESARETNAM, K., GUTHRIE, N., CHAMBERS, A.F., CARROLL, K.K., Effect of tocotrienols on the growth of a human breast cancer cell line in culture, Lipids 30 12 (1995) 1139.

[65] NESARETNAM, K., STEPHEN, R., DILS, R., DARBRE, P., Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status, Lipids 33 5 (1998) 461.

[66] YU, W. et al., Anticancer actions of natural and synthetic vitamin E forms: RRR-alpha-tocopherol blocks the anticancer actions of gamma-tocopherol, Mol. Nutr. Food Res. 53 12 (2009) 1573.

[67] ADACHI, H., ISHII, N., Effects of tocotrienols on life span and protein carbonylation in Caenorhabditis elegans, J. Gerontol. A Biol. Sci. Med. Sci. 55 6 (2000) B280.

[68] HENNEKENS, C.H. et al., Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease, N. Engl. J. Med. 334 18 (1996) 1145.

[69] GREEN, A. et al., Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial, Lancet 354 9180 (1999) 723.

[70] LEE, I.M., COOK, N.R., MANSON, J.E., BURING, J.E., HENNEKENS, C.H., Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women’s Health Study, J. Natl. Cancer Inst. 91 24 (1999) 2102.

[71] GREENBERG, E.R. et al., A Clinical Trial of Beta Carotene to Prevent Basal-Cell and Squamous-Cell Cancers of the Skin, N. Engl. J. Med. 323 12 (1990) 789.

[72] SATIA, J.A., LITTMAN, A., SLATORE, C.G., GALANKO, J.A., WHITE, E., Long-term use of beta-carotene, retinol, lycopene, and lutein supplements and lung cancer risk: results from the VITamins And Lifestyle (VITAL) study, Am. J. Epidemiol. 169 7 (2009) 815.

[73] GALLICCHIO, L. et al., Carotenoids and the risk of developing lung cancer: a systematic review, Am. J. Clin. Nutr. 88 2 (2008) 372.

[74] STÄHELIN, H.B. et al., Plasma antioxidant vitamins and subsequent cancer mortality in the 12-year follow-up of the prospective Basel Study, Am. J. Epidemiol. 133 8 (1991) 766.

[75] MICHAUD, D.S. et al., Intake of specific carotenoids and risk of lung cancer in 2 prospective US cohorts, Am. J. Clin. Nutr. 72 4 (2000) 990.

[76] ELIASSEN, A.H. et al., Circulating carotenoids and risk of breast cancer: pooled analysis of eight prospective studies, J. Natl. Cancer Inst. 104 24 (2012) 1905.

[77] GREENBERG, E.R. et al., Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation, JAMA 275 9 (1996) 699.

[78] YUAN, J.-M. et al., Prediagnostic levels of serum micronutrients in relation to risk of gastric cancer in Shanghai, China, Cancer Epidemiol. Biomarkers Prev. 13 11 Pt 1 (2004) 1772.

[79] GEY, K.F., STÄHELIN, H.B., EICHHOLZER, M., Poor plasma status of carotene and vitamin C is associated with higher mortality from ischemic heart disease and stroke: Basel Prospective Study, Clin. Investig. 71 1 (1993) 3.

[80] D’ODORICO, A. et al., High plasma levels of alpha- and beta-carotene are associated with a lower risk of atherosclerosis: results from the Bruneck study, Atherosclerosis 153 1 (2000) 231.

[81] SAHYOUN, N.R., JACQUES, P.F., RUSSELL, R.M., Carotenoids, vitamins C and E, and mortality in an elderly population, Am. J. Epidemiol. 144 5 (1996) 501.

[82] YUSUF, S., DAGENAIS, G., POGUE, J., BOSCH, J., SLEIGHT, P., Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators, N. Engl. J. Med. 342 3 (2000) 154.

[83] SALONEN, J.T. et al., Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study: a randomized trial of the effect of vitamins E and C on 3-year progression of carotid atherosclerosis, J. Intern. Med. 248 5 (2000) 377.

[84] LAI, G.Y. et al., Effects of α-tocopherol and β-carotene supplementation on liver cancer incidence and chronic liver disease mortality in the ATBC study, Br. J. Cancer 111 12 (2014) 2220.

[85] PETERSEN, R.C. et al., Vitamin E and donepezil for the treatment of mild cognitive impairment, N. Engl. J. Med. 352 23 (2005) 2379.

[86] GISSI-PREVENZIONE INVESTIGATORS, Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico, Lancet 354 9177 (1999) 447.

[87] DE GAETANO, G., COLLABORATIVE GROUP OF THE PRIMARY PREVENTION PROJECT, Low-Dose Aspirin and Vitamin E in People at Cardiovascular Risk: A Randomised Trial in General Practice. Collaborative Group of the Primary Prevention Project, The Lancet, Vol. 357 (2001) pp. 89–95.

[88] GAZIANO, J.M. et al., Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians’ Health Study II randomized controlled trial, JAMA 301 1 (2009) 52.

[89] KUSHI, L.H. et al., Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women, N. Engl. J. Med. 334 18 (1996) 1156.

[90] LEE, I.-M. et al., Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial, JAMA 294 1 (2005) 56.

[91] LIPPMAN, S.M. et al., Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT), JAMA 301 1 (2009) 39.

[92] EIDELMAN, R.S., HOLLAR, D., HEBERT, P.R., LAMAS, G.A., HENNEKENS, C.H., Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease, Arch. Intern. Med. 164 14 (2004) 1552.

[93] MILLER, E.R., 3rd et al., Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality, Ann. Intern. Med. 142 1 (2005) 37.

[94] BOAZ, M. et al., Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial, Lancet 356 9237 (2000) 1213.

[95] NESARETNAM, K., SELVADURAY, K.R., ABDUL RAZAK, G., VEERASENAN, S.D., GOMEZ, P.A., Effectiveness of tocotrienol-rich fraction combined with tamoxifen in the management of women with early breast cancer: a pilot clinical trial, Breast Cancer Res. 12 5 (2010) R81.

[96] GOPALAN, Y. et al., Clinical investigation of the protective effects of palm vitamin E tocotrienols on brain white matter, Stroke 45 5 (2014) 1422.

[97] HENG, E.C. et al., Supplementation with tocotrienol-rich fraction alters the plasma levels of Apolipoprotein A-I precursor, Apolipoprotein E precursor, and C-reactive protein precursor from young and old individuals, Eur. J. Nutr. 52 7 (2013) 1811.

[98] CHIN, S.-F. et al., Tocotrienol rich fraction supplementation improved lipid profile and oxidative status in healthy older adults: A randomized controlled study, Nutr. Metab. 8 1 (2011) 42.

[99] RASOOL, A.H.G., RAHMAN, A.R.A., YUEN, K.H., WONG, A.R., Arterial compliance and vitamin E blood levels with a self emulsifying preparation of tocotrienol rich vitamin E, Arch. Pharm. Res. 31 9 (2008) 1212.

[100] TOMEO, A.C., GELLER, M., WATKINS, T.R., GAPOR, A., BIERENBAUM, M.L., Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis, Lipids 30 12 (1995) 1179.

[101] PATEL, V. et al., Oral tocotrienols are transported to human tissues and delay the progression of the model for end-stage liver disease score in patients, J. Nutr. 142 3 (2012) 513.

[102] ARGUILLAS, M., The effect of vitamin E (mixed tocotrienol) on the liver stiffness measurement measured by transient elastography (fibroScan) among NAFLD patients, APAS Liver Week Singapore (2013).

[103] MAGOSSO, E. et al., Tocotrienols for normalisation of hepatic echogenic response in nonalcoholic fatty liver: a randomised placebo-controlled clinical trial, Nutr. J. 12 1 (2013) 166.

[104] GEE, P.T., Unleashing the untold and misunderstood observations on vitamin E, Genes Nutr. 6 1 (2011) 5.

[105] STAHL, W. et al., Carotenoid mixtures protect multilamellar liposomes against oxidative damage: synergistic effects of lycopene and lutein, FEBS Lett. 427 2 (1998) 305.

[106] THOMAS, S.R., NEUZIL, J., MOHR, D., STOCKER, R., Coantioxidants make alpha-tocopherol an efficient antioxidant for low-density lipoprotein, Am. J. Clin. Nutr. 62 6 Suppl (1995) 1357S.

[107] PALOZZA, P., Can β-carotene regulate cell growth by a redox mechanism? An answer from cultured cells, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1740 2 (2005) 215.

[108] DEVASAGAYAM, T.P.A. et al., Free radicals and antioxidants in human health: current status and future prospects, J. Assoc. Physicians India 52 (2004) 794.

[109] COLLINS, A.R., AZQUETA, A., LANGIE, S.A.S., Effects of micronutrients on DNA repair, Eur. J. Nutr. 51 3 (2012) 261.

[110] STIDLEY, C.A. et al., Multivitamins, folate, and green vegetables protect against gene promoter methylation in the aerodigestive tract of smokers, Cancer Res. 70 2 (2010) 568.

[111] GERSON, C., Healing Lung Cancer and Respiratory Disease the Gerson Way, Gerson Health Media (2002).

[112] GERSON, M., GERSON, C., A Cancer Therapy: Results of Fifty Cases ; And, the Cure of Advanced Cancer by Diet Therapy : A Summary of 30 Years of Clinical Experimentation, Gerson Institute educational video series, Gerson Institute (1958).

[113] GERSON, C., SHWED, J., KROSCHEL, S., Healing the Gerson Way (with DVD): Defeating Cancer and Other Chronic Diseases, Gerson Health Media (2011).

[114] USDA, USDA National Nutrient Database for Standard Reference, Release 26 (2013).

[115] THOMAS, S.R., NEUZIL, J., STOCKER, R., Cosupplementation with coenzyme Q prevents the prooxidant effect of alpha-tocopherol and increases the resistance of LDL to transition metal-dependent oxidation initiation, Arterioscler. Thromb. Vasc. Biol. 16 5 (1996) 687.

[116] BROWN, K.M., MORRICE, P.C., DUTHIE, G.G., Erythrocyte vitamin E and plasma ascorbate concentrations in relation to erythrocyte peroxidation in smokers and nonsmokers: dose response to vitamin E supplementation, Am. J. Clin. Nutr. 65 2 (1997) 496.

[117] LEE, R., MARGARITIS, M., CHANNON, K.M., ANTONIADES, C., Evaluating oxidative stress in human cardiovascular disease: methodological aspects and considerations, Curr. Med. Chem. 19 16 (2012) 2504.

[118] MOLAVI, B., MEHTA, J.L., Oxidative stress in cardiovascular disease: molecular basis of its deleterious effects, its detection, and therapeutic considerations, Curr. Opin. Cardiol. 19 5 (2004) 488.

[119] WHITE, W.S., STACEWICZ-SAPUNTZAKIS, M., ERDMAN, J.W., Jr, BOWEN, P.E., Pharmacokinetics of beta-carotene and canthaxanthin after ingestion of individual and combined doses by human subjects, J. Am. Coll. Nutr. 13 6 (1994) 665.

[120] HANDELMAN, G.J., MACHLIN, L.J., FITCH, K., WEITER, J.J., DRATZ, E.A., Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans, J. Nutr. 115 6 (1985) 807.

[121] KOSTIC, D., WHITE, W.S., OLSON, J.A., Intestinal absorption, serum clearance, and interactions between lutein and a-carotene when administered to human adults in separate or combined oral doses1, Am J Clin NuIr 62 (1995) 604.

[122] LANDES, N. et al., Vitamin E activates gene expression via the pregnane X receptor, Biochem. Pharmacol. 65 2 (2003) 269.

[123] PRINCE, M.R., FRISOLI, J.K., Beta-carotene accumulation in serum and skin, Am. J. Clin. Nutr. 57 2 (1993) 175.

[124] MICOZZI, M.S. et al., Plasma carotenoid response to chronic intake of selected foods and beta-carotene supplements in men, Am. J. Clin. Nutr. 55 6 (1992) 1120.

[125] XU, M.J. et al., Reduction in plasma or skin alpha-tocopherol concentration with long-term oral administration of beta-carotene in humans and mice, J. Natl. Cancer Inst. 84 20 (1992) 1559.

[126] 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, Dietary Reference Intakes, National Academies Press (2001).

[127] Federal Register | Food Labeling: Revision of the Nutrition and Supplement Facts Labels, https://www.federalregister.gov/articles/2014/03/03/2014-04387/food-labeling-revision-of-the-nutrition-and-supplement-facts-labels#h-50.

[128] CDC, Second National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population, National Center for Environmental Health (2012).

[129] DONALDSON, M.S., A carotenoid health index based on plasma carotenoids and health outcomes, Nutrients 3 12 (2011) 1003.

[130] LI, C. et al., Serum α-carotene concentrations and risk of death among US Adults: the Third National Health and Nutrition Examination Survey Follow-up Study, Arch. Intern. Med. 171 6 (2011) 507.

[131] MIN, K.-B., MIN, J.-Y., Serum carotenoid levels and risk of lung cancer death in US adults, Cancer Sci. 105 6 (2014) 736.

[132] NAGATA, C. et al., Serum carotenoids and vitamins and risk of cervical dysplasia from a case-control study in Japan, Br. J. Cancer 81 7 (1999) 1234.

[133] SHARDELL, M.D. et al., Low-serum carotenoid concentrations and carotenoid interactions predict mortality in US adults: the Third National Health and Nutrition Examination Survey, Nutr. Res. 31 3 (2011) 178.

[134] MUSTAD, V.A., SMITH, C.A., RUEY, P.P., EDENS, N.K., DEMICHELE, S.J., Supplementation with 3 compositionally different tocotrienol supplements does not improve cardiovascular disease risk factors in men and women with hypercholesterolemia, Am. J. Clin. Nutr. 76 6 (2002) 1237.

[135] QURESHI, A.A. et al., Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols (palmvitee), Am. J. Clin. Nutr. 53 4 Suppl (1991) 1021S.

[136] ONG, A.S.H., NIKI, E., PACKER, L., “Tocopherols and tocotrienols in key foods in the US diet”, Nutrition, Lipids, Health, and Disease (ONG, A.S.H., NIKI, E., Eds), AOCS Press (1995).

[137] HEINONEN, M., PIIRONEN, V., The tocopherol, tocotrienol, and vitamin E content of the average Finnish diet, Int. J. Vitam. Nutr. Res. 61 1 (1991) 27.

[138] SOOKWONG, P. et al., Tocotrienol distribution in foods: estimation of daily tocotrienol intake of Japanese population, J. Agric. Food Chem. 58 6 (2010) 3350.

[139] NOWICKA, B., GRUSZKA, J., KRUK, J., Function of plastochromanol and other biological prenyllipids in the inhibition of lipid peroxidation—A comparative study in model systems, Biochimica et Biophysica Acta (BBA) - Biomembranes 1828 2 (2013) 233.

[140] MUKAI, K., ITOH, S., MORIMOTO, H., Stopped-flow kinetic study of vitamin E regeneration reaction with biological hydroquinones (reduced forms of ubiquinone, vitamin K, and tocopherolquinone) in solution, J. Biol. Chem. 267 31 (1992) 22277.

[141] BUETTNER, G.R., The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate, Arch. Biochem. Biophys. 300 2 (1993) 535.

[142] ITOH, S., NAGAOKA, S.-I., MUKAI, K., Kinetic study of the tocopherol regeneration reaction by biological hydroquinones in micellar solution, J. Phys. Chem. A 112 3 (2008) 448.

[143] PODDA, M., WEBER, C., TRABER, M.G., PACKER, L., Simultaneous determination of tissue tocopherols, tocotrienols, ubiquinols, and ubiquinones, J. Lipid Res. 37 4 (1996) 893.

[144] NAFEEZA, M.I., KANG, T.T., Synergistic effects of tocopherol, tocotrienol, and ubiquinone in indomethacin-induced experimental gastric lesions, Int. J. Vitam. Nutr. Res. 75 2 (2005) 149.

[145] BENTINGER, M., BRISMAR, K., DALLNER, G., The antioxidant role of coenzyme Q, Mitochondrion 7 Suppl (2007) S41.

[146] BEN-AMOTZ, A., LEVY, Y., Bioavailability of a natural isomer mixture compared with synthetic all-trans beta-carotene in human serum, Am. J. Clin. Nutr. 63 5 (1996) 729.

[147] LEVIN, G., MOKADY, S., Antioxidant activity of 9-cis compared to all-trans beta-carotene in vitro, Free Radic. Biol. Med. 17 1 (1994) 77.

[148] GAZIANO, J.M. et al., Supplementation with beta-carotene in vivo and in vitro does not inhibit low density lipoprotein oxidation, Atherosclerosis 112 2 (1995) 187.

[149] MOBARHAN, S. et al., Effects of beta-carotene repletion on beta-carotene absorption, lipid peroxidation, and neutrophil superoxide formation in young men, Nutr. Cancer 14 3-4 (1990) 195.

[150] PALOZZA, P., Prooxidant actions of carotenoids in biologic systems, Nutr. Rev. 56 9 (1998) 257.

[151] STOCKER, R., BOWRY, V.W., FREI, B., Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol, Proc. Natl. Acad. Sci. U. S. A. 88 5 (1991) 1646.

[152] GARDEN OF LIFE, The Vitamin Code.

[153] LIU, R.H., Dietary bioactive compounds and their health implications, J. Food Sci. 78 Suppl 1 (2013) A18.

[154] TIWARI, B.K., BRUNTON, N.P., BRENNAN, C., Handbook of Plant Food Phytochemicals: Sources, Stability and Extraction, Wiley (2013).

[155] WATANABE, F., Vitamin B12 sources and bioavailability, Exp. Biol. Med. 232 10 (2007) 1266.

[156] WALTHER, B., KARL, J.P., BOOTH, S.L., BOYAVAL, P., Menaquinones, bacteria, and the food supply: the relevance of dairy and fermented food products to vitamin K requirements, Adv. Nutr. 4 4 (2013) 463.