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beta carotene

GlossarySuccess Chemistry Staff

beta carotene is a fat-soluble

plant pigment found in red, orange, and yellow vegetables

and fruits.

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,

and tissues.

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

among them.

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.

 

BIOAVAILABILITY

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).

  • 115

  • 116 Johnson and Russell

  • 8′COOH

  • 10′CHO 10′COOH

  • 8′CHO

  • 15′ 14′ 12′ 10′ 8′

  • 12′CHO

  • CHO

  • CH2OH COOH

  • Retinal

  • Retinol Retinoic Acid

  • β-Carotene

  • 12′COOH

  • 14′COOH

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

Food Sources

-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

beta carotene

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.

Recommended Intakes

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

harmful.

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).

 

Cancer Prevention

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.

Cardiovascular Disease

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

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,

30 mg/day

5

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.

 

CONTRAINDICATIONS

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

deaths

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.

 

TOXICITY/ADVERSE EFFECTS

-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

carotenodermia.

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

β-Carotene 119

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

this time.

 

COMPENDIAL/REGULATORY STATUS

-Carotene is in the generally recognized as safe (GRAS)

list issued by the Food and Drug Administration.

 

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120 Johnson and Russell

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FURTHER READING

1. Kritchevsky SB. Beta-carotene, carotenoids and the prevention

of cardiovascular disease. J Nutr 1999; 129:5–8.

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