beta carotene is a fat-soluble
plant pigment found in red, orange, and yellow vegetables
beta carotene is converted to vitamin A (retinal,
retinol, and retinoic acid), when it is in short supply in
the body. It is an antioxidant—a compound that blocks
the action of activated oxygen molecules that can damage
cells. Dietary intake of foods containing -carotene has
been associated with cancer prevention. However, there
is not enough evidence to support this. In fact, high-dose
beta carotene supplementation may increase the risk of lung
cancer among people already at high risk, such as smokers.
BIOCHEMISTRY AND FUNCTIONS
beta carotene belongs to a large class of plant pigments referred
to as carotenoids. It is made up of eight isoprene
units that are cyclized at each end of the molecule. –
Carotene functions in plants and in photosynthetic bacteria
as an accessory pigment in photosynthesis and protects
against photosensitization in animals, plants, and bacteria.
In humans, the only known function of -carotene is
its vitamin A activity. Other possible actions in humans
include antioxidant activity, immunoenhancement, inhibition
of mutagenesis and transformation, inhibition of
premalignant lesions, and decreased risk of some cancers
and some cardiovascular events. In the skin, -carotene
has been found to have protective effects against solar radiation
damage. However, two human intervention studies
that used high-dose beta carotene supplements reported
an increased risk for lung cancer among smokers (1,2).
In vitro and in vivo studies suggest the potential chemopreventive
activity of -carotene; that is, -carotene itself
may act as an anti carcinogen, but its oxidized products,
which appear when -carotene is present in tissue at high
concentration, may facilitate carcinogenesis (3).
ABSORPTION AND METABOLISM
Because -carotene is fat soluble, it follows the same
intestinal absorption pathway as dietary fat. Release of
-carotene from the food matrix and its dissolution in
the lipid phase are the important initial steps in the absorption
process. -Carotene is thought to be absorbed by
the small intestinal mucosa via a passive, diffusion process.
It is taken up by the mucosa of the small intestine
and packaged into triacylglycerol-rich chylomicrons and
is partly converted to vitamin A by a specific enzyme,
-carotene 15,15-oxygenase (also known as carotene
mono-oxygenase or CMOI), in the intestinal mucosa. Both
-carotene and vitamin A (primarily as retinyl esters) are
incorporated into chylomicrons and secreted into lymph
for transport to the liver. A second cleavage enzyme
(CMOII) cleaves -carotene eccentrically at the 9–10 position
to yield -apo-10-carotenal and -ionone. The significance
of this reaction is uncertain, but it is clear that
CMOII is a minor player with respect to the formation of
vitamin A. Additional random oxidative cleavage at several
double bonds in the polyene chain of -carotene can
also occur when there is not an adequate supply of antioxidants,
for example, vitamin E. However, enzymatic central
cleavage by CMOII plays the major role in -carotene
breakdown under normal conditions. In conditions of oxidative
stress (e.g., smoking or diseases associated with oxidative
stress) or when high concentrations of -carotene
are present, both central and random cleavage may occur
(Fig. 1) (4).
The delivery of beta carotene to extrahepatic tissue
is accomplished through the interaction of lipoprotein
particles with receptors and the degradation of lipoproteins
by extrahepatic enzymes such as lipoprotein lipase.
-Carotene is present in a number of human tissues, including
adipose, liver, kidney, adrenal gland, and testes
and is one of the major carotenoids in human diet, serum,
In fasting serum, -carotene is found primarily in
low-density lipoproteins (LDL), but appreciable amounts
are also found in high-density lipoproteins (HDL) (5–7).
-Carotene, being lipophilic, is located in the core of
lipoproteins, which may explain why there is little transfer
The concentration of -carotene in human serum
is highly variable and depends on a number of factors,
including -carotene intake, efficiency of absorption, and
other components of the diet.
The bioavailability of a carotenoid is considered to be the
fraction of ingested carotenoid utilized for normal physiological
functions or storage. Information on carotenoid
bioavailability is based largely on serum levels after ingestion.
The bioavailability of -carotene from food, concentrated
extracts, or synthetic products is quite variable.
Several human studies have reported on the serum
response to -carotene supplements. Factors that affect
-carotene bioavailability include vehicle type (supplement
vs. food: processed vs. unprocessed food) and dietary
factors (amount of -carotene, fat, and fiber) (8).
- 116 Johnson and Russell
- 10′CHO 10′COOH
- 15′ 14′ 12′ 10′ 8′
- CH2OH COOH
- Retinol Retinoic Acid
Figure 1 -Carotene conversion to vitamin A (retinal, retinol, and retinoic acid). Central cleavage by carotene monooxygenase or CMOI between bonds 15 and
15 forms retinal directly. A second cleavage enzyme (CMOII) cleaves -carotene eccentrically at the 9–10 position. Cleavage at other bonds forms apocarotenoids
(CHO). Apocarotenoids may be oxidized to apocarotenoid acids (–COOH), which could form retinoic acid. Apocarotenoids may be oxidized to apocarotenoid acids
(–COOH), which could form retinoic acid.
Compared with carrots (a source of -carotene),
supplements suspended in oil or in water from gelatin stabilized
beadlets (the form used in the major clinical
trials) raise the plasma concentration approximately sixfold.
This may be because a pure form of -carotene does
not need to be released from a food matrix for intestinal
absorption. -Carotene may have twice the bioavailability
from fruits compared with green leafy vegetables. The percentage
absorption of a single dose of -carotene (45 mg
to 39 mg) has been reported to range from 9% to 22%
(9–11), but the absorption efficiency decreases as the
amount of carotenoids in the diet increases (12–15). Absorption
of -carotene at dosages greater than 20 to 30 mg
is very limited because of the factors such as solubility (16).
Cooking and mechanical homogenization increase
the bioavailability of carotenoids from foods. The mechanism
by which this occurs is most likely the disruption
of the food matrix to release the carotenoid from
the matrix and from protein complexes. For example,
the plasma response of -carotene has been reported to
be three times greater in spinach and carrots that were
pureed and thermally processed than it was when these
vegetables were consumed in raw, large pieces (17). Although
dietary fat facilitates the absorption of -carotene,
the amount of dietary fat does not affect the postprandial
increases in plasma -carotene concentrations, as
long as there is some fat in the diet (18). However, when
-carotene is given in the absence of fat, no detectable
change in serum level occurs (19). Studies involving daily
supplementation with high-dose -carotene on plasma
concentrations of other carotenoids for several years find
no overall adverse effect on plasma concentrations of
other carotenoids (20). The -carotene: vitamin A (retinol)
equivalency ratio of a low dose (<2 mg) of purified –
carotene in oil is approximately 2:1. The water miscible
form of -carotene is presumed to be better absorbed than
the carotenoid in oil and, therefore, may have a more
efficient (i.e., lower) conversion ratio. However, the efficiency
of absorption of -carotene in food is lower than
that of -carotene in oil. The Institute of Medicine of the
National Academy of Sciences proposes that 12 mg of
-carotene in food has the same vitamin A activity as
1 mg retinol (21).
INDICATIONS AND USAGE
-Carotene is the most widely studied carotenoid and
is one of the major carotenoids in our diet and in human
blood and tissues (22,23). Major sources of dietary
-carotene include green leafy vegetables as well as orange
and yellow fruits and vegetables (Table 1) (24). However,
the bioavailability of -carotene from green leafy
Table 1 -Carotene Content of Foods (24)
Food Content (mg/100 g wet weight)a
- Carrots, raw 7.9
- Carrots, cooked 9.8
- Apricots, raw 3.5
- Apricots, dried 17.6
- Cantaloupe, raw 3.0
- Kale 4.7
- Pepper, red 2.2
- Pumpkin 3.1
- Spinach, raw 4.1
- Spinach, cooked 5.5
- Sweet potato, cooked 8.8
- Winter squash, cooked 2.4
a Edible portion.
vegetables such as spinach is thought to be low with a
conversion factor of carotene to retinol of 20:1, whereas
the conversion factor from fruit may be somewhat better
(on the order of 12:1) (25). As discussed above, factors
other than food vehicle are thought to be important in the
bioavailability of -carotene. These include cooking, chopping,
and the presence of dietary fat, all of which improve
the bioavailability (17,26). Of the 50 different carotenoids
that can be metabolized into vitamin A, -carotene has
the highest provitamin A activity. Genetically engineered
“Golden Rice” contains up to 35 g of -carotene per
gram rice (27), with a the conversion factor of Golden Rice
-carotene to retinol in adults of 3.8:1, with a range of 1.9–
6.4:1 by weight. Typical dietary intakes of -carotene in
the United States are 0.5 to 6.5 mg/day (28–30). However,
intakes much higher than this are possible through overthe-
counter supplements, which are commonly available
in health food stores in doses of 3 to 20 mg/capsule.
Although at present no dietary reference intakes (DRIs)
are proposed for -carotene, existing recommendations
for increased consumption of carotenoid-rich fruits and
vegetables are supported. Based on the evidence that –
carotene supplements have not been shown to provide
any benefit for the prevention of major chronic diseases
and may cause harm in certain subgroups (e.g., smokers
and asbestos workers), it is concluded that -carotene
supplements are not advisable other than as a source of
provitamin A. If there is adequate retinol in the diet, there
are no known clinical effects of consuming diets low or
moderate in -carotene. -Carotene is widely used in vitamin
and mineral supplements at levels ranging from 0.4
to 20 mg/day. It is given medicinally in doses of up to
6 mg/day for dietary deficiency of vitamin A (although
preformed vitaminAis usually used for this purpose) and
up to 300 mg/day for the reduction of photosensitivity in
individuals with erythropoietic protoporphyria.
Although no safe upper level of intake for -carotene
has been established in the United States, the European
Expert Group on Vitamins and Minerals has established a
safe upper level of -carotene intake of 7 mg/day (31). The
safe upper level applies only to the general population,
that is, nonsmokers and those not exposed to asbestos
and to -carotene supplements only, given that there is no
evidence to suggest that -carotene intake from foods are
Excessive dietary intake of preformed vitaminAhas
been associated with reduced bone mineral density and
increased risk of hip fractures. -Carotene may be a safe
source of vitamin A in osteoporotic subjects, given that it
is not associated with bone demineralization (32).
Observational epidemiologic studies have been very consistent
in showing that people who consume higher dietary
levels of fruits and vegetables have a lower risk of
certain types of cancer (33). The consistency of the results
is particularly strong for lung cancer, in which carotenoid
and/or fruit and vegetable intake has been associated with
reduced risk in all of 8 prospective studies and in 18 of 20
retrospective studies (34). However, in three large randomized
clinical trials using high-dose -carotene supplements
(20 mg/day, 30 mg/day, or 50 mg given every
other day for 4–12 years), no protection was reported with
respect to lung cancer or any other cancer (1,2,35). In fact,
in two of these studies, there was an increased risk of
lung cancer in heavy smokers and asbestos workers with
-carotene supplementation (1,2) (see “Contraindications”).
More recently, it was reported that longer duration
of use of individual -carotene supplements (but not total
10-year average dose) was associated with statistically significantly
elevated risk of total lung cancer (36). However,
there was little evidence for effect modification by gender
or smoking status.
A body of evidence indicating that the oxidation of LDL
plays an important role in the development of atherosclerosis
has led investigators to consider a preventive role
for -carotene. Early in vitro studies of LDL oxidation
showed that -carotene carried in LDL is oxidized before
the onset of oxidation of LDL polyunsaturated fatty acids,
suggesting a possible role in delaying LDL oxidation.
Epidemiologic studies, including descriptive, cohort, and
case-control studies, suggest that -carotene–rich diets are
associated with a reduced risk of cardiovascular disease
(37–39). Furthermore, inverse association between serum
or adipose -carotene levels and cardiovascular outcomes
has also been observed. However, in a meta-analysis of
eight -carotene treatment trials involving 138,113 subjects,
a dose range of 15 to 50 mg/day and follow-up
range from 1.4 to 12.0 years, it was found that -carotene
supplementation led to a small but significant increase in
all-cause mortality and a slight but significant increase in
cardiovascular death (40).
Erythropoietic protoporphyria is an inborn defect of ferrochelatase
resulting in an increase in the protoporphyrin
content of the erythrocytes, plasma, and feces. The disease
is characterized clinically by photosensitivity, which
generally appears within the first few years of life. These
patients experience a burning sensation of the skin within
a few minutes or hours of exposure to sunlight, followed
by edema, erythema, and purpura. -Carotene has been
used therapeutically for the treatment of erythropoietic
118 Johnson and Russell
Table 2 -Carotene Supplementation Trials: Study Designs
Study (Ref.) Population Intervention Duration (yr)
ATBC (2) 29,133 Finnish male smokers (50–69 yr of age) -Carotene, 20 mg/day; vitamin E, 50 mg/day 5–8
CARET (1) 18,314 men and women and asbestos workers
(45–74 yr of age)
-Carotene, 30 mg/day; vitamin A, 25,000 IU <4
PHS (35) 22,071 male physicians (40–84 yr of age) -Carotene, 50 mg on alternate days 12
Linxian (42) 29,584 men and women, vitamin and mineral
deficient (40–69 yr)
-Carotene, 15 mg/day; selenium, 50 mg/day; -tocopherol,
protoporphyria (41). This is based on the observation that
carotenoids prevent photosensitivity in bacteria. On treatment
of the condition with extremely high doses (up to
300 mg/day) of -carotene, a marked improvement in
skin photosensitivity has been reported in some, but not
all, patients. No toxic effects have been in the limited number
of patients reported.
The epidemiologic observations of possible protective effects
of high dietary (not supplemental) -carotene intakes
against cancer, along with what is known about carotenoid
biochemical functions, has led to further study of the effect
of -carotene on cancer risk. Long-term large randomized
intervention trials were designed to test the efficacy of
high doses of -carotene (20–30 mg/day) in the prevention
of cancer (Table 2). As stated above, the results from two
trials provided possible evidence of harm from -carotene
supplements in relation to cancer among high-risk individuals,
such as smokers and asbestos workers (1,2), but
no effect (either beneficial or detrimental) in a generally
well-nourished population (34). Moreover, in the Linxian
(Chinese) Cancer Prevention Study (42), it was found
that supplementation with -carotene doses, vitamin E,
and selenium led to a significant reduction in total mortality
(9%), especially from cancer (13%) and particularly
stomach cancer (21%) (Table 3). The positive results of the
Chinese study probably reflect the correction of a vitamin
A deficiency in this study population. A number of mechanisms
have been proposed to account for the association
between -carotene supplementation and lung cancer in
smokers and asbestos workers, including an imbalance of
other carotenoids or antioxidants, a pro-oxidant activity
of -carotene at the high oxygen tensions found in the
lungs, induction of P450 enzymes, and the production of
damaging -carotene oxidation products by components
of cigarette smoke (3).
The epidemiologic studies that led to these intervention
studies reported an inverse relationship between diet
Table 3 -Carotene Supplementation Trial: Cancer Outcomes
Study (Ref.) Cancer outcome
ATBC (2) 18% increase in lung cancer; 8% increase in mortality
CARET (1) 28% increase in lung cancer; 17% increase in deaths
PHS (35) No effect of supplementation on incidence of cancer
Linxian (42) 13% decrease in total cancers; 9% decrease in overall
and/or blood -carotene levels and cancer prevention. It is
probable that -carotene serves as a marker of increased
fruit and vegetable intake and, therefore, of all components
that have cancer prevention potential, for example,
vitamin C, folic acid, other carotenoids, and polyphenols.
Alternatively, low-dose dietary levels could have a protective
effect against cancer, whereas high-dose supplement
-carotene could have a cancer stimulating effect.
-Carotene obtained from eating fruits and vegetables is
considered safe. -Carotene first became available as a
pharmaceutical product in the early 1970s. It can be purified
from natural sources such as green plants or algae,
or it can be manufactured synthetically. Purity of
-carotene may be a problem when derived from plant
or algal sources. Preparations of crystalline -carotene in
oil are widely available. Although not harmful, high doses
of -carotene (from foods and supplements) can result in
a skin condition known as carotenodermia, in which the
skin turns to yellow–orange color due to an elevation of
plasma and tissue carotene concentrations. Carotenodermia
is reversible when -carotene ingestion is discontinued.
This condition has been reported in adults taking
supplements containing 20 to 30 mg/day or more of –
carotene for long periods of time or consuming high levels
of carotenoid-rich foods such as carrots (43) and is
the primary effect of excess carotenoid intake noted in infants,
toddlers, and young children (44). Carotenodermia
is distinguished from jaundice in that the ocular sclerae
are yellowed in jaundiced subjects but not in those with
In the treatment of erythropoietic protoporphyria
(180 mg/day), no toxic effects have been observed for very
high doses of -carotene (41). However, the number of
patients studied has been small. There is no evidence that
-carotene is teratogenic, mutagenic, or carcinogenic in
long-term bioassays in experimental animals (45). In humans,
there have been no reports of reproductive toxicity
or teratogenicity associated with high -carotene intake,
either before or during pregnancy. In addition, long-term
supplementation with -carotene to persons with adequate
vitaminA status does not increase the concentration
of serum retinol, as the metabolic conversion is regulated
by vitaminA status, that is, the better the vitaminA status,
the lower the conversion to vitamin A (20).
Doses of 20 to 30 mg/day of -carotene for 4 to 12
years have been associated with an increased risk of lung
cancer in high-risk groups (i.e., smokers and asbestos exposed
workers). Similar to the results in human
intervention studies, carotene supplementation for several
months (at doses equivalent to a 30-mg dose in man)
to ferrets exposed to cigarette smoke resulted in the development
of squamous cell metaplasia in the lungs of ferrets
(46). The development of squamous cell metaplasia was
also observed in animals supplemented with -carotene
(at the same dose as above) without exposure to smoke, although
the metaplasia was less prominent. Whether high,
chronic doses of -carotene in low-risk groups, for example,
nonsmokers, would have toxic effects is not known at
-Carotene is in the generally recognized as safe (GRAS)
list issued by the Food and Drug Administration.
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