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Title
Antioxidant actions of beta-carotene in liposomal and microsomal
membranes: role of carotenoid-membrane incorporation and alpha-tocopherol.
Author
Liebler DC; Stratton SP; Kaysen KL
Address
College of Pharmacy, University of Arizona, Tucson, Arizona,
85721-0207, USA.
Source
Arch Biochem Biophys, 338(2):244-50 1997 Feb 15
Abstract
beta-Carotene and other carotenoids are widely regarded as biological
antioxidants. However, recent clinical trials indicate that beta-carotene
supplements are not effective in disease prevention and raise
questions about the biological significance of carotenoid antioxidant
actions. To further explore this issue, we have reevaluated the
antioxidant actions of beta-carotene in liposomal and biological
membrane systems. In dilinoleoylphosphatidylcholine liposomes
in which 0.35 mol % beta-carotene was incorporated into the bilayer
during liposome preparation, the carotenoid inhibited lipid peroxidation
initiated by 10 mm azobisÍamidinopropane HClÍ (AAPH).
In carotenoid-free liposome suspensions to which the same amount
of beta-carotene was added, no antioxidant effect was observed.
Supplementation of rat liver microsomes with beta-carotene in
vitro yielded microsomes containing 1.7 nmol beta-carotene mg-1
and 0.16 nmol alpha-tocopherol mg-1 microsomal protein. In beta-carotene
supplemented microsomes incubated with 10 mm AAPH under an air
atmosphere, lipid peroxidation did not occur until alpha-tocopherol
was depleted by approximately 60%. beta-Carotene exerted no apparent
antioxidant effect and was not significantly depleted in the
incubations. Similar results were obtained when the incubation
was done at 3.8 torr O2. In liver microsomes from Mongolian gerbils
fed beta-carotene-supplemented diets, beta-carotene levels were
16-37% of alpha-tocopherol levels. The kinetics of AAPH-induced
lipid peroxidation were no different in beta-carotene-supplemented
microsomes than in microsomes from unsupplemented animals, although
the kinetics of beta-carotene and alpha-tocopherol depletion
were similar. The results indicate that beta-carotene is ineffective
as an antioxidant when added to preformed lipid bilayer membranes
and that alpha-tocopherol is a much more effective membrane antioxidant
than beta-carotene, regardless of the method of carotenoid-membrane
incorporation. These results support a reevaluation of the proposed
antioxidant role for beta-carotene in biological membranes.
Title
Kinetics of parallel electron transfer from beta-carotene to
phenoxyl radical and adduct formation between phenoxyl radical
and beta-carotene.
Author
Mortensen A; Skibsted LH
Address
Department of Dairy and Food Science, Royal Veterinary and Agricultural
University, Frederiksberg, Denmark.
Source
Free Radic Res, 25(6):515-23 1996 Dec
Abstract
Phenoxyl radicals generated by laser flash photolysis were found
to react with beta-carotene with concomitant beta-carotene bleaching
in two parallel reactions with similar rates: (i) formation of
a beta-carotene adduct with a (pseudo) first order rate constant
of 1-1.5 x 10(4) s-1 with absorption maximum around 800 nm, and
(ii) formation of a beta-carotene radical cation with a (pseudo)
first order rate constant of 2-3 x 10(4) s-1 with absorption
maximum around 920 nm. Both beta-carotene radicals decay on a
similar time scale and have virtually disappeared after 100 ms,
the beta-carotene adduct by a second order process. Oxygen had
no effect on beta-carotene bleaching or radical formation and
decay. The reduction of phenoxyl radicals by beta-carotene may
prove important for an understanding of how beta-carotene acts
as an antioxidant.
Title
Alpha-Tocopherol and beta-carotene supplements and lung cancer
incidence in the alpha-tocopherol, beta-carotene cancer prevention
study: effects of base-line characteristics and study compliance
[seecomments]
Author
Albanes D; Heinonen OP; Taylor PR; Virtamo J; Edwards BK; Rautalahti
M; Hartman AM; Palmgren J; Freedman LS; Haapakoski J; Barrett
MJ; Pietinen P; Malila N; Tala E; Liippo K; Salomaa ER; Tangrea
JA; Teppo L; Askin FB; Taskinen E; Erozan Y; Greenwald P; Huttunen
JK
Address
Division of Cancer Prevention and Control, National Cancer Institute,
Bethesda, MD 20892-7326, USA.
Source
J Natl Cancer Inst, 88(21):1560-70 1996 Nov 6
Abstract
BACKGROUND: Experimental and epidemiologic investigations suggest
that alpha-tocopherol (the most prevalent chemical form of vitamin
E found in vegetable oils, seeds, grains, nuts, and other foods)
and beta-carotene (a plant pigment and major precursor of vitamin
A found in many yellow, orange, and dark-green, leafy vegetables
and some fruit) might reduce the risk of cancer, particularly
lung cancer. The initial findings of the Alpha-Tocopherol, Beta-Carotene
Cancer Prevention Study (ATBC Study) indicated, however, that
lung cancer incidence was increased among participants who received
beta-carotene as a supplement. Similar results were recently
reported by the Beta-Carotene and Retinol Efficacy Trial (CARET),
which tested a combination of beta-carotene and vitamin A. PURPOSE:
We examined the effects of alpha-tocopherol and beta-carotene
supplementation on the incidence of lung cancer across subgroups
of participants in the ATBC Study defined by base-line characteristics
(e.g., age, number of cigarettes smoked, dietary or serum vitamin
status, and alcohol consumption), by study compliance, and in
relation to clinical factors, such as disease stage and histologic
type. Our primary purpose was to determine whether the pattern
of intervention effects across subgroups could facilitate further
interpretation of the main ATBC Study results and shed light
on potential mechanisms of action and relevance to other populations.
METHODS: A total of 29,133 men aged 50-69 years who smoked five
or more cigarettes daily were randomly assigned to receive alpha-tocopherol
(50 mg), beta-carotene (20 mg), alpha-tocopherol and beta-carotene,
or a placebo daily for 5-8 years (median, 6.1 years). Data regarding
smoking and other risk factors for lung cancer and dietary factors
were obtained at study entry, along with measurements of serum
levels of alpha-tocopherol and beta-carotene. Incident cases
of lung cancer (n = 894) were identified through the Finnish
Cancer Registry and death certificates. Each lung cancer diagnosis
was independently confirmed, and histology or cytology was available
for 94% of the cases. Intervention effects were evaluated by
use of survival analysis and proportional hazards models. All
P values were derived from two-sided statistical tests. RESULTS:
No overall effect was observed for lung cancer from alpha-tocopherol
supplementation (relative risk [RR] = 0.99; 95% confidence interval
[CI] = 0.87-1.13; P = .86, logrank test). beta-Carotene supplementation
was associated with increased lung cancer risk (RR = 1.16; 95%
CI = 1.02-1.33; P = .02, logrank test). The beta-carotene effect
appeared stronger, but not substantially different, in participants
who smoked at least 20 cigarettes daily (RR = 1.25; 95% CI =
1.07-1.46) compared with those who smoked five to 19 cigarettes
daily (RR = 0.97; 95% CI = 0.76-1.23) and in those with a higher
alcohol intake (> or = 11 g of ethanol/day [just under one
drink per day]; RR = 1.35; 95% CI = 1.01-1.81) compared with
those with a lower intake (RR = 1.03; 95% CI = 0.85-1.24). CONCLUSIONS:
Supplementation with alpha-tocopherol or beta-carotene does not
prevent lung cancer in older men who smoke. beta-Carotene supplementation
at pharmacologic levels may modestly increase lung cancer incidence
in cigarette smokers, and this effect may be associated with
heavier smoking and higher alcohol intake. IMPLICATIONS: While
the most direct way to reduce lung cancer risk is not to smoke
tobacco, smokers should avoid high-dose beta-carotene supplementation.
Title
Risk factors for lung cancer and for intervention effects in
CARET, the Beta-Carotene and Retinol Efficacy Trial [see comments]
Author
Omenn GS; Goodman GE; Thornquist MD; Balmes J; Cullen MR; Glass
A; Keogh JP; Meyskens FL Jr; Valanis B; Williams JH Jr; Barnhart
S; Cherniack MG; Brodkin CA; Hammar S
Address
Division of Public Health Sciences, Fred Hutchinson Cancer Research
Center, Seattle, WA 98104, USA.
Source
J Natl Cancer Inst, 88(21):1550-9 1996 Nov 6
Abstract
BACKGROUND: Evidence has accumulated from observational studies
that people eating more fruits and vegetables, which are rich
in beta-carotene (a violet to yellow plant pigment that acts
as an antioxidant and can be converted to vitamin A by enzymes
in the intestinal wall and liver) and retinol (an alcohol chemical
form of vitamin A), and people having higher serum beta-carotene
concentrations had lower rates of lung cancer. The Beta-Carotene
and Retinol Efficacy Trial (CARET) tested the combination of
30 mg beta-carotene and 25,000 IU retinyl palmitate (vitamin
A) taken daily against placebo in 18314 men and women at high
risk of developing lung cancer. The CARET intervention was stopped
21 months early because of clear evidence of no benefit and substantial
evidence of possible harm; there were 28% more lung cancers and
17% more deaths in the active intervention group (active = the
daily combination of 30 mg beta-carotene and 25,000 IU retinyl
palmitate). Promptly after the January 18, 1996, announcement
that the CARET active intervention had been stopped, we published
preliminary findings from CARET regarding cancer, heart disease,
and total mortality. PURPOSE: We present for the first time results
based on the pre-specified analytic method, details about risk
factors for lung cancer, and analyses of subgroups and of factors
that possibly influence response to the intervention. METHODS:
CARET was a randomized, double-blinded, placebo-controlled chemoprevention
trial, initiated with a pilot phase and then expanded 10-fold
at six study centers. Cigarette smoking history and status and
alcohol intake were assessed through participant self-report.
Serum was collected from the participants at base line and periodically
after randomization and was analyzed for beta-carotene concentration.
An Endpoints Review Committee evaluated endpoint reports, including
pathologic review of tissue specimens. The primary analysis is
a stratified logrank test for intervention arm differences in
lung cancer incidence, with weighting linearly to hypothesized
full effect at 24 months after randomization. Relative risks
(RRs) were estimated by use of Cox regression models; tests were
performed for quantitative and qualitative interactions between
the intervention and smoking status or alcohol intake. O'Brien-Fleming
boundaries were used for stopping criteria at interim analyses.
Statistical significance was set at the .05 alpha value, and
all P values were derived from two-sided statistical tests. RESULTS:
According to CARET's pre-specified analysis, there was an RR
of 1.36 (95% confidence interval [CI] = 1.07-1.73; P = .01) for
weighted lung cancer incidence for the active intervention group
compared with the placebo group, and RR = 1.59 (95% CI = 1.13-2.23;
P = .01) for weighted lung cancer mortality. All subgroups, except
former smokers, had a point estimate of RR of 1.10 or greater
for lung cancer. There are suggestions of associations of the
excess lung cancer incidence with the highest quartile of alcohol
intake (RR = 1.99; 95% CI = 1.28-3.09; test for heterogeneity
of RR among quartiles of alcohol intake has P = .01, unadjusted
for multiple comparisons) and with large-cell histology (RR =
1.89; 95% CI = 1.09-3.26; test for heterogeneity among histologic
categories has P = .35), but not with base-line serum beta-carotene
concentrations. CONCLUSIONS: CARET participants receiving the
combination of beta-carotene and vitamin A had no chemopreventive
benefit and had excess lung cancer incidence and mortality. The
results are highly consistent with those found for beta-carotene
in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study
in 29133 male smokers in Finland. IMPLICATIONS: Individuals at
high risk of developing lung cancer, i.e., current smokers and
asbestos-exposed workers, should be discouraged from taking supplemental
beta-carotene (and the combination of beta-carotene with vitamin
A). Safety and efficacy should be demonstrated befor
Title
The effect of orlistat, an inhibitor of dietary fat absorption,
on the pharmacokinetics of beta-carotene in healthy volunteers.
Author
Zhi J; Melia AT; Koss-Twardy SG; Arora S; Patel IH
Address
Hoffmann-La Roche, Inc., Nutley, New Jersey 07110-1199, USA.
Source
J Clin Pharmacol, 36(2):152-9 1996 Feb
Abstract
To assess the influence of orlistat, a lipase inhibitor, on the
absorption of beta-carotene, an open-label, parallel, placebo-controlled,
randomized, two-way crossover study was performed in 48 healthy
volunteers between the ages of 19 and 58 years. Each subject
received a single oral dose of 0, 30, 60, or 120 mg beta-carotene
(12 subjects per dose level) on the fourth day of treatment with
orlistat (120 mg) or placebo 3 times a day for 6 days. The treatments
were separated by a washout period of at least 5 weeks. Serial
blood samples were collected before and at appropriate intervals
after administration of beta-carotene to determine plasma concentrations
of unchanged beta-carotene. Short-term (3 to 6 days) treatment
with orlistat did not alter endogenous profiles of beta-carotene
in plasma. When beta-carotene was given during orlistat treatment,
its absorption was reduced by approximately one-third. This reduction
was consistent for all three dose levels of beta-carotene studied;
however, the results for the 30-mg dose level were subject to
greater variability, particularly for area under the concentration-time
curve (AUC). It was concluded that two thirds of a supplemental
dose of beta-carotene will be absorbed during orlistat treatment;
this may be sufficient to achieve physiologic levels of beta-carotene
with an appropriate dose of beta-carotene, should supplementation
be needed in obese patients who have developed beta-carotene
deficiency during therapy with orlistat.
Title
In vitro beta-carotene toxicity for human colon cancer cells.
Author
Iftikhar S; Lietz H; Mobarhan S; Frommel TO
Address
Department of Medicine, Columbus Cabrini Hospital, Chicago, IL
60614,USA.
Source
Nutr Cancer, 25(3):221-30 1996
Abstract
Experiments were conducted to determine the effect of beta-carotene
on human colon cancer cells in vitro. beta-Carotene solubilized
in tetrahydrofuran (THF) was determined to be cytotoxic for three
different cell lines: LS 180, SW 620, and HCT-15. The number
of LS 180 and SW 620 cells surviving treatment with 2.9 microM
beta-carotene was significantly reduced relative to THF-treated
cells, and a similar reduction was achieved in HCT-15 cells with
use of 5.8 microM beta-carotene. These concentrations are in
the range achieved in serum of individuals supplemented with
beta-carotene at 30 mg/day. There was no beta-carotene cytotoxicity
in the concentration range that characterizes serum of unsupplemented
individuals. Vitamin E at > 200 microM was not cytotoxic and
at higher concentrations slightly stimulated proliferation of
all three cell lines. Exposure of cells to vitamin E did not
diminish the cytotoxicity of beta-carotene, suggesting that the
toxic effect of beta-carotene is not due to prooxidant activity.
Percent cytotoxicity was increased by extending the duration
of exposure of cells to beta-carotene. Interestingly, beta-carotene
cytotoxicity decreased with increasing cell density. This density-dependent
toxicity was attributable to a higher beta-carotene concentration
per cell for cells plated at lower densities. Thus toxicity of
beta-carotene for colon cancer cells is dose, time, and cell
density dependent and occurs in vitro at concentrations that
can be achieved safely in humans.
Title
Gastric acidity influences the blood response to a beta-carotene
dose in humans.
Author
Tang G; Serfaty-Lacrosniere C; Camilo ME; Russell RM
Address
Jean Mayer US Department of Agriculture Human Nutrition Research
Center on Aging, Tufts University, Boston, MA 02111. Tang_HP@HNRC.Tufts.edu
Source
Am J Clin Nutr, 64(4):622-6 1996 Oct
Abstract
The effect of gastric acidity on the blood response to a single
dose of 120 mg beta-carotene in humans was investigated in 12
normal subjects (5 women, 7 men) aged 23-68 y. Omeprazole was
used for 7 d to obliterate gastric acid secretion and to raise
gastric pH to > 4.5. In a crossover design, six subjects were
randomly assigned to take beta-carotene with omeprazole either
at the beginning (day 9) or at the end (day 26) of the study.
The beta-carotene response in blood was not altered by the experimental
order. Results from the high-gastric-pH phase (ie, with omeprazole)
were analyzed together and compared with the results from the
low-gastric-pH phase (ie, without omeprazole). The increases
of serum concentrations of both trans beta-carotene and cis beta-carotene
6 and 24 h after the beta-carotene dose were significantly greater
at a low gastric pH (pH = 1.3 +/- 0.1, ie, without omeprazole)
than those at a high gastric pH (pH = 6.4 +/- 0.3, ie, with omeprazole),
P < 0.02. Similarly, 24 h after beta-carotene administration,
the area under the blood beta-carotene response curve (trans
plus cis beta-carotene) was significantly greater at a low gastric
pH (6825 +/- 760 nmol.h/L) than at a high gastric pH (3390 +/-
550 nmol.h/L), P < 0.002. In investigations of bacterial overgrowth,
gelatin capsule disintegration and isomeric profiles associated
with high and low pH, we could not identify factors to explain
the differences observed in the blood response curves between
low-gastric-pH and high-gastric-pH conditions. A suppressed blood
response of beta-carotene at a high intraluminal pH may have
been due to the slower movement of negatively charged micelles
through the unstirred water layer and cell membrane.
Title
The effect of supplemental beta-carotene on immunologic indices
in patients with AIDS: a pilot study.
Author
Fryburg DA; Mark RJ; Griffith BP; Askenase PW; Patterson TF
Address
Division of Endocrinology and Metabolism, Yale University School
of Medicine, New Haven, Connecticut, USA.
Source
Yale J Biol Med, 68(1-2):19-23 1995 Jan-Apr
Abstract
Patients with the acquired immunodeficiency syndrome (AIDS) are
characterized by a decrease in the number of T helper cells,
a defect that is linked to the impaired immunologic competence.
Vitamin A and its dietary precursor, beta-carotene, increase
absolute T helper cell counts as well as indices of T cell function
in both human and animal models. To determine if short-term beta-carotene
treatment affects T lymphocyte subsets in patients with AIDS,
a single-blind, non-randomized clinical trial of beta-carotene
was performed in seven patients with AIDS. Enrollment criteria
included no evidence of: a) active opportunistic infection: b)
greater than 1 kilogram change in weight in the month preceding
enrollment; c) chronic diarrhea or malabsorption; and d) hepatic
disease or significant anemia. Beta-carotene was given with meals
in two divided doses of 60 mg/day for four weeks; this was followed
by no therapy for six weeks. Samples for total white blood cell,
lymphocyte and T lymphocyte subset counts were measured at baseline,
at the end of four weeks of treatment and another six weeks after
treatment had stopped. P24 antigen, beta-2 microglobulin and
liver function tests were also measured. All subjects tolerated
the treatment well without evidence of toxicity. In response
to beta-carotene, total lymphocyte counts rose by 66 percent
(.05 < p < .10), and CD4+ cells rose slightly, but insignificantly,
in the entire group. In all three of the patients who had baseline
CD4+ cells greater than 10/microliters, however, the mean absolute
increase in CD4+ cells in response to beta-carotene was 53 +/-
10 cells/microliters (p < .01). Six weeks off beta-carotene
treatment, the absolute CD4+ cell count returned to pretreatment
levels (p < .01). No change was observed in CD8+ cells. P24
antigen and beta-2 microglobulin did not change during treatment.
These preliminary observations suggest that short-term treatment
with beta-carotene may increase CD4+ cell counts in patients
with AIDS who have greater than 10 cells/microliters. |
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