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Procter & Gamble Miami Valley Laboratories, Cincinnati, OH 45253-8707
1To whom correspondence should be addressed.
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INTRODUCTION |
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 TOP INTRODUCTION {beta}-Carotene degradation.Degradation of {beta}-carotene...Reduced levels of {beta}...Are {beta}-carotene degradation...The "Sentinel" Hypothesis.REFERENCES |
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,
Shekelle et al. 1981
). Studies have shown that diets
high in fruits and vegetables containing ß-carotene were associated
with a reduced risk of cancer and other diseases (Block et al. 1992
).
Diet and epidemiology studies have not, however, been able to confirm
that ß-carotene is a principal factor in the reduced risk of disease.
Intervention trials designed to test the hypothesis of the protective
nature of dietary ß-carotene resulted in data suggestive of an
increased rather than a decreased risk of cancer with ß-carotene
supplementation (Alpha Tocopherol Beta Carotene Cancer Prevention Study Group 1994
, Omenn et al. 1996
).
In addition to investigations of effects of dietary ß-carotene, the relation of serum or tissue levels of ß-carotene to disease has also been studied. A focus on this relationship suggests the following hypothesis: tissue concentrations of ß-carotene may be indicators of cellular insult. This hypothesis is suggested by the lability of ß-carotene, which is readily susceptible to oxidation and other chemical transformation. Its chemical fragility can make ß-carotene the sentinel of the cell, serving as the canary, whose sensitivity to methane signaled alarm to coal miners. Low levels of ß-carotene may reflect the effect of disease rather than the cause.
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ß-Carotene degradation. |
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TOPINTRODUCTION{beta}-Carotene degradation.Degradation of {beta}-carotene...Reduced levels of {beta}...Are {beta}-carotene degradation...The "Sentinel" Hypothesis.REFERENCES |
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). Cell membrane disruption takes place with oxidation of the unsaturated fatty acid moieties of the phospholipids in the membrane bilayers. Cellular ß-carotene can be affected by these same oxidative processes, and its reactions could follow any or all of three paths discussed below: protectant, reactant, or prooxidant.
i) Protectant. The ß-carotene could protect membrane
chains by forming a free radical that ends the chain reaction of free
radicals in the membrane. The concentration of ß-carotene would
decrease as it is used up by combining with free radicals. According to
the scheme shown by Burton and Ingold (1984)
, ß-carotene
(ßC)2
can react with a peroxyl radical, ROO·, to produce the
radical species, ROO-ßC·, and the formation of this
product is accompanied by a reduction in unreacted ß-carotene.
ii) Reactant. The ß-carotene could be oxidized faster than
other unsaturated molecules in the cell. The ß-carotene concentration
would decrease and its oxidation products would accumulate in the cell.
These products could be beneficial, neutral or detrimental to the cell.
Examples of detrimental effects were reported by Wang et al. (1999)
.
Their data suggest that the apocarotenoids (produced by cigarette
smoke) "might cause diminished retinoid signaling by
down-regulating retanoic acid receptor ß (RARß) expression and
the retinoic acid level in lung tissue and by upregulating activator
protein-1 (AP-1)." They also proposed that the apocarotenoid
products, such as ß-apo-8'-carotenal, induce cytochrome P450 enzymes
that destroy retinoic acid.
iii) Prooxidant. As Palozzo reported (Palozzo 1998
), ß-carotene could undergo autoxidation when the
ßC· and ROO-ßC· radicals combine with
molecular oxygen in an environment of sufficient oxygen partial
pressure (as in the lung). These species could also act as prooxidants
in propagating the oxidation of unsaturated fatty acids. Both
autoxidation and prooxidation reactions result in a decrease in
unreacted ß-carotene.
In any or all of these roles involving cellular oxidation, the concentration of ß-carotene would decrease. Examples of reactions that take place in the cell to reduce ß-carotene levels are given below.
Kikugawa and coworkers studied the effect of NO2
and peroxynitrous acid (ONOOH) on ß-carotene (Kikugawa et al. 1997
). Using electron spin resonance spectroscopy they
found that nitrogen atoms from nitrogen dioxide were bound to
ß-carotene and thereby decreased the concentration of unreacted
ß-carotene. They also found that 
-tocopherol did not affect the
loss of ß-carotene.
Kennedy and Liebler (1992)
studied ß-carotene in soybean
phosphatidylcholine liposomes. They generated peroxyl radicals with an
initiator of lipid peroxidation, azo-bis
2,4-dimethylvaleronitrile. The ß-carotene inhibited peroxidation
of linoleic acid moieties. More inhibition was seen at 3.3 and 21.5 kPa
than at 101.3 kPa O2. The reaction resulted in depletion of
ß-carotene and the formation of polar products including an epoxide
of ß-carotene. The authors concluded antioxidant protection would be
provided by ß-carotene in the physiologic range of oxygen partial
pressure, pO2. They also found that there was a
"background" oxidation of ß-carotene that was unrelated to the
initiator and that ß-carotene-derived peroxy radicals reacted more
rapidly with ß-carotene than with other unsaturated lipids in the
system. This latter observation points to the instability of
ß-carotene relative to the other lipids and another pathway for
depletion of ß-carotene.
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Degradation of ß-carotene in biological samples. |
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TOPINTRODUCTION{beta}-Carotene degradation.Degradation of {beta}-carotene...Reduced levels of {beta}...Are {beta}-carotene degradation...The "Sentinel" Hypothesis.REFERENCES |
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-tocopherol), Engberg et al. (1996)
observed a fall
in tissue and plasma ß-carotene. The concentration of ß-carotene in
plasma from the chickens fed oxidized oil was less than half of that of
those fed fresh oil. A similar reduction was seen in the ß-carotene
concentrations in the abdominal fat.
Liebler et al. (1996)
reported studies of ß-carotene both in
liposomes and in microsomal membranes of rats and gerbils. The
liposomes were made from dilinoeylphosphatidylcholine with 0.35 g/100 g
of ß-carotene. In the liposomes, ß-carotene inhibited peroxidation
accelerated by an initiator. Two types of microsome preparations were
studied. Rat liver microsomes that were supplemented with ß-carotene
in vitro contained 1.7 nmol of ß-carotene and 0.16 nmol of
-tocopherol per mg of protein. In these microsomes, peroxidation did
not occur until -tocopherol was depleted. The ß-carotene did not
inhibit peroxidation and was not depleted in the incubations. Similar
results were seen in an atmosphere of air and at 0.51 kPa
pO2. Liver microsomes from gerbils contained
ß-carotene that had been incorporated from the diet rather than in
vitro as in the rat microsomes. Rates of initiated peroxidation were
the same in gerbil microsomes that were supplemented and
unsupplemented, and the depletions of ß-carotene and of
-tocopherol were similar. This depletion is consistent with a
reduced level of ß-carotene reflecting cellular oxidation. The
authors also concluded that -tocopherol is much more effective as a
membrane antioxidant than ß-carotene.
In another example of destruction of ß-carotene in a lipid-rich
particle, Panasenko et al. (1997)
reported the decrease of ß-carotene
in LDL that was reacted with hypochlorite (HOCl). HOCl is produced in
vivo by the neutrophil-derived enzyme myeloperoxidase, and may be
involved in a number of host-defense cellular reactions
(Wahn and Hammerschmidt 1998
).
Palozza et al. (1997)
studied the effects of pO2
on the antioxidant effects of ß-carotene in murine normal and tumor
thymocytes. They found that pO2 markedly
influenced the effects of ß-carotene. At 101.3 kPa
pO2, ß-carotene doubled the initiated lipid
oxidation in tumor cells but not in normal cells. At 20.0 kPa
pO2, ß-carotene did not alter the lipid
oxidation. Incubation of normal and tumor cells without an initiator
decreased ß-carotene content at all levels of
pO2 with little difference between normal and
tumor cells. When an initiator was present, ß-carotene concentrations
fell more rapidly, and the concentration in tumor cells decreased
faster than that in normal cells. At 20.0 kPa pO2
the concentration of ß-carotene fell to 40% of the beginning level
in 60 min in the tumor cells while the concentration in the normal
cells decreased to ~80% of the initial level. In tumor cells
(induced to oxidation with xanthine/xanthine oxidase), the addition of
ß-carotene decreased the concentration of endogenous -tocopherol
by 20% in 15 min. Tumor thymocytes had significantly higher levels of
-tocopherol relative to the normal cells.
Day et al. (1998)
studied ß-carotene in HL-60 cells that remained
viable in the presence of peroxyl radicals. They measured oxidative
stress in cell membrane phospholipids with a fluorescent fatty acid
(cis-parinaric acid). After establishing the viability of
the cells, they found that ß-carotene at levels of 0–1.5
nmol/106 cells was consumed and had no effect on
the oxidation of cis-parinaric acid. In the same conditions,
-tocopherol was effective as an antioxidant at levels as low as 0.25
nmol/106 cells. The authors concluded "that
ß-carotene has no antioxidant activity in cells under normobaric
conditions, and that it likely has in fact prooxidant properties with
respect to cellular phospholipids." The conclusion about prooxidant
properties is based on the observation of consumption of the
ß-carotene molecules that apparently participated in lipid
peroxidation.
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Reduced levels of ß-carotene in humans in disease and chemical insult. |
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TOPINTRODUCTION{beta}-Carotene degradation.Degradation of {beta}-carotene...Reduced levels of {beta}...Are {beta}-carotene degradation...The "Sentinel" Hypothesis.REFERENCES |
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resulted in an important observation.
Breast adipose tissue from 46 breast cancer cases was compared with
that of 63 control subjects (benign breast disease). There were
significantly lower concentrations of ß-carotene (and of retinyl
palmitate, lycopene, and lutein/zeaxanthin) in the patients relative to
controls. The age-adjusted and multivariate-adjusted odds
ratios for breast cancer in relation to breast adipose concentration
were ~0.3 for ß-carotene and lycopene levels greater than the
median relative to those less than the median. Importantly, daily intakes (diet plus supplement) of ß-carotene and all carotenoids were the same for cases and controls. The enrollment in the study took place in two parts, and the results were analyzed separately as "Batch 1" and "Batch 2" from the two enrollment periods. In Batch 1 the cases ate 9.12 µmol/d of ß-carotene compared with 7.862 µmol/d, for the controls. In Batch 2, the comparable values were 8.038 µmol/d and 7.518 µmol/d. Analogous values for cases and controls for lycopene were 8.382 µmol/d, 8.714 µmol/d (Batch 1) and 7.827 µmol/d, 7.889 µmol/d (Batch 2). The Pearson correlation coefficient between ß-carotene intake and ß-carotene in adipose tissue in 48 control subjects gave a value of 0.08 for multivariate-adjusted r2, showing a diet to be a poor predictor of the tissue levels.
The data are therefore consistent with the hypothesis that ß-carotene is an indicator of cellular insult reflecting the effect of disease rather than cause. Levels of tissue ß-carotene in breast cancer cases were lower than those of control subjects when ß-carotene intake was not different between the two groups.
van’t Veer et al. (1996)
found no relationship of breast cancer to
levels of ß-carotene in subcutaneous adipose tissue from the buttocks
in 347 patients and 374 control subjects. This result differs from that
of Zhang et al. (1997)
but may reflect the different sites of tissue
samples in the two trials.
The Alpha Tocopherol Beta Carotene (ATBC) study results also suggest
that that low levels of ß-carotene are indicative of disease (Alpha Tocopherol Beta Carotene Cancer Prevention Study Group 1994
). The
placebo group in the ATBC study, which received no ß-carotene
supplementation, was divided into quartiles based on entry levels of
serum ß-carotene and -tocopherol. The incidence of lung cancer was
higher among the subjects in the lowest quartile than in those in the
highest (incidence per 10,000 person-years, lowest vs. highest:
-tocopherol 61.4 vs. 40.6; ß-carotene, 47.9 vs. 39.9). The dietary
intake of ß-carotene for this group or its quartiles was not
published. Diet could have influenced the serum levels in the placebo
group, but it is also possible that low serum ß-carotene reflected
incipient cancer that was later observed.
Decreased levels of ß-carotene in tissues of smokers have been
observed in many (Benton et al. 1997
, Marangon et al. 1998
, Pamuk et al. 1994
, Roidt et al. 1988
) but not all (Nierenberg et al. 1989
)
studies. Although this frequent observation may be the result of a
number of factors, it is consistent with the attack of ß-carotene by
free radicals generated in smoke and consistent with the hypothesis
that chemical insult lowers blood and tissue ß-carotene levels.
Mikhail et al. (1994)
reported low levels of ß-carotene in exfoliated
vaginal epithelial cells in cases of vaginal candidiasis. These cells
from 22 women with diagnosed vaginal candidiasis and 20 control
subjects were analyzed for ß-carotene. The concentration in the
patients was significantly less (P < 0.001) than that
of the controls. There was no information about dietary intake of
ß-carotene. If intakes were comparable, however, the observation
would be consistent with disease-induced reduction of cellular
ß-carotene.
Decreased levels of ß-carotene were observed in patients with acute
myocardial infarction relative to control subjects (Levy et al. 1998
). The patients’ values were significantly less than those
of the controls, 2.03 nmol/L vs. 3.22 nmol/L. Dietary intake of
ß-carotene was not measured.
Palan et al. (1989)
reported decreased ß-carotene levels in uterine
leiomyomas and other cancers. The ß-carotene concentration was lower
in fibroid tissue than in normal myometrium (P = 0.0013). They also found lower levels of ß-carotene in tissues of
cancers of the cervix, endometrium, ovary, breast, colon, lung, liver
and rectum. Dietary ß-carotene was not estimated.
Stich et al. (1986)
reported lower levels of ß-carotene in oral
mucosal cells of men who consumed 150 g of alcohol per week (0.15
pmol/106 cells) relative to nondrinking males
(2.31 pmol/106 cells). This observation is
consistent with other reports of the effects of alcohol on ß-carotene
levels (Benton et al. 1997
) and suggests that ethanol
results in degradation of cellular ß-carotene.
Oxidative stress resulting from iron overload in tissues results in
depletion of tissue ß-carotene. Livrea et al. (1996)
found a
reduction of 29% in serum ß-carotene from thalassemia patients
relative to control subjects. The authors concluded that high iron
concentrations resulting from continuous blood transfusions depleted
lipid-soluble antioxidants.
Saintot and coworkers (1999) reported the measurement of ozone exposure
and plasma carotenoids in 58 subjects in France. They found that there
was a significant negative regression coefficient between ozone
exposure and plasma -carotene (r = -0.39,
P < 0.01) or ß-carotene (r = -0.45,
P = 0.02). In a subset of nonsmoking subjects with low
ß-carotene levels, exposure to low levels of ozone significantly
reduced plasma levels of ß-carotene.
Although studies have often found a positive relation between dietary
intake and serum levels of certain carotenoids (Ascherio et al. 1992
), there have been exceptions to this generalization. For
example, Roidt et al. (1988)
reported very weak correlations between
dietary ß-carotene intake and serum ß-carotene. It is possible that
exceptions to the direct relationship of dietary and tissue
ß-carotene may result from degradation of ß-carotene that is
unrelated to the diet.
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Are ß-carotene degradation products detrimental? |
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TOPINTRODUCTION{beta}-Carotene degradation.Degradation of {beta}-carotene...Reduced levels of {beta}...Are {beta}-carotene degradation...The "Sentinel" Hypothesis.REFERENCES |
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, Omenn et al. 1996
).
The mechanism by which ß-carotene may have increased the incidence of
cancer in smokers was elucidated by Wang et al. (1999)
. As noted
earlier, these workers proposed that apocarotenoids are formed by
reactions initiated by free radicals produced by cigarette smoke. They
further proposed that apocarotenoids induce cytochrome P450 that
destroys retinoic acid and also upregulate AP-1. Studies reporting
other detrimental effects of ß-carotene or its oxidation products are
cited below.
As noted earlier, Palozzo et al. (1997)
found increased levels of
ß-carotene caused a reduction in -tocopherol levels. Palozzo (1998)
reviewed studies of animals fed ß-carotene and noted that in
six of seven studies, plasma levels of -tocopherol decreased as a
result of dietary ß-carotene at levels ranging from 0.1 to 10 g/kg of
diet.
Leo et al. (1997)
reported that ß-carotene increased hepatotoxic
effects of alcohol. In rats fed alcohol and ß-carotene, glutamate
dehydrogenase increased with the dose of ß-carotene. The authors note
that "it remains to be determined whether the undesirable effects
also pertain to ß-carotene-rich foods or to individuals consuming
ß-carotene in the absence of beadlets with or without alcohol."
Xu et al. (1992)
studied long-term oral ingestion of ß-carotene
in humans and in mice. These workers found significant decreases of
-tocopherol in plasma and skin, an observation consistent with
destruction of -tocopherol by ß-carotene.
Salgo et al. (1998)
found the binding of benzo[a]pyrene metabolites
to calf thymus DNA when ß-carotene oxidation products were present
(in the absence of NADPH) increased to 3.3 times the value observed for
the control without ß-carotene or its oxidation products. This result
contrasted with a nonsignificant 19% decrease in this binding when
unoxidized ß-carotene was present.
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The "Sentinel" Hypothesis. |
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TOPINTRODUCTION{beta}-Carotene degradation.Degradation of {beta}-carotene...Reduced levels of {beta}...Are {beta}-carotene degradation...The "Sentinel" Hypothesis.REFERENCES |
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FOOTNOTES |
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Manuscript received August 16, 1999. Initial review completed October 6, 1999. Revision accepted October 28, 1999.
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REFERENCES |
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TOPINTRODUCTION{beta}-Carotene degradation.Degradation of {beta}-carotene...Reduced levels of {beta}...Are {beta}-carotene degradation...The "Sentinel" Hypothesis.REFERENCES |
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