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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
Effects of dietary beta-carotene and selenium on initiation and
promotion of pancreatic carcinogenesis in azaserine-treated rats.
Author
Appel MJ; Woutersen RA
Address
Department of General Toxicology, TNO Nutrition and Food Research
Institute, The Netherlands.
Source
Carcinogenesis, 17(7):1411-6 1996 Jul
Abstract
In the present study the effects of 0.1 or 1.0 g beta-carotene/kg
diet (L beta C or H beta C) and 1.0 mg or 2.5 mg selenium/kg
diet (LSel or HSel), as well as combinations of the respective
low and high concentrations of beta-carotene and selenium (LMix
or HMix) on the initiation/early promotion phase or on the late
promotion phase of pancreatic carcinogenesis in azaserine-treated
rats, were investigated using cell proliferation and volumetric
data of atypical acinar cell foci (AACF) as parameters. The present
results indicate chemopreventive effects of dietary selenium,
dietary beta-carotene and of their combination on the development
of acinar pancreatic lesions induced in rats by azaserine. The
inhibitory effect was most pronounced when beta-carotene and/or
selenium were added to the diets during the late promotion phase
of the carcinogenic process, although inhibition was also observed
with these compounds when they were added to the diets during
the first 5 weeks of the study only (initiation/early promotion
phase). Neither in the initiation/early promotion phase nor in
the late promotion phase was a dose-related trend observed. The
multiplicities of AACF with a diameter over 1.0 mm and of carcinomas
in situ (CIS), as well as the incidence of CIS were not significantly
different among the groups. However, in the late promotion experiment
a dose-related decline in multiplicity could be observed in the
selenium supplemented groups and in the groups receiving combinations
of beta-carotene and selenium. Cell proliferation in azaserine-induced
AACF, as estimated by the bromodeoxyuridine (BrdU) labeling index,
was significantly higher in H beta C, HSel, LMix and HMix groups
(initiation/early promotion phase) as well as in H beta C, LSel,
HSel, LMix and HMix groups (late promotion phase) than in high
fat controls. From the present results it can be concluded that:
(i) beta-carotene and selenium have inhibitory effects on pancreatic
carcinogenesis induced in rats by azaserine; (ii) the most clear
effects were observed when selenium was given as such, or in
combination with beta-carotene during the late promotion phase;
and (iii) beta-carotene and selenium stimulate cell proliferation
in AACF.
Title
Beta-carotene serum levels in patients with erythropoietic protoporphyria
on treatment with the synthetic all-trans isomer or a natural
isomeric mixture of beta-carotene.
Author
von Laar J; Stahl W; Bolsen K; Goerz G; Sies H
Address
Institut für Physiologische Chemie I, Heinrich-Heine-University
Düsseldorf, Germany.
Source
J Photochem Photobiol B, 33(2):157-62 1996 Apr
Abstract
The all-trans-beta-carotene serum level of patients suffering
from erythropoietic protoporphyria increases substantially during
continuous treatment with beta-carotene (either with the synthetic
all-trans compound or with beta-carotene from a natural Source
consisting of a cis-trans isomeric mixture). On continuous daily
ingestion, the beta-carotene serum level rose from day 0 to day
30, and no further increase was observed between day 30 and day
150. Slightly lower beta-carotene steady state serum levels were
observed with the natural isomeric mixture than with synthetic
beta-carotene. Higher levels of 13-cis-beta-carotene, in some
cases up to 10% of the total beta-carotene, were detected after
ingestion of the synthetic compound. The level of 9-cis-beta-carotene
was below or close to the limit of quantification in all samples,
even when the isomeric mixture containing high amounts of 9-cis-beta-carotene
was applied.
Title
In vitro measurement of beta-carotene cleavage activity: methodological
considerations and the effect of other carotenoids on beta-carotene
cleavage.
Author
van Vliet T; van Schaik F; Schreurs WH; van den Berg H
Address
Department of Physiology and Kinetics, TNO Nutrition and Food
Research Institute, AJ Zeist, The Netherlands.
Source
Int J Vitam Nutr Res, 66(1):77-85 1996
Abstract
In view of controversies about assessment of the beta-carotene
cleavage activity, methodological aspects and problems of the
dioxygenase assay are described. Using rat and hamster intestinal
preparations the method was optimized on retinal formation, the
only cleavage product we could demonstrate. It appeared that
the cell fraction with the highest cleavage activity was the
9,000 g supernatant (S-9). Maximal retinal formation was obtained
with SDS, taurocholate and egg lecithin in the buffer and 3 micrograms
beta-carotene dissolved in acetone. Ethanol, THF/DMSO (1:1) or
propylene glycol as solvent for beta-carotene reduced retinal
formation to 55, 24, and 19%, respectively. Retinal formation
increased proportionally with the amount of protein S-9 used
and was linear up to 40-60 minutes of incubation. Incubation
with alpha-carotene or beta-cryptoxanthin resulted in a retinal
formation of 29 and 55% of the amount formed from beta-carotene.
Addition of 9 micrograms of lutein to an incubation with 3 micrograms
beta-carotene reduced retinal formation, while lycopene had no
effect. In conclusion, the beta-carotene cleavage assay with
S-9 as enzyme Source described in this report, seems a
useful tool to study (dietary) determinants of beta-carotene
cleavage activity, but for other purposes adaptation of the method
is required.
Title
beta-Carotene absorption and cleavage in rats is affected by
the vitamin A concentration of the diet.
Author
van Vliet T; van Vlissingen MF; van Schaik F; van den Berg H
Address
Department of Physiology and Kinetics, TNO Nutrition and Food
Research Institute, Zeist, Netherlands.
Source
J Nutr, 126(2):499-508 1996 Feb
Abstract
The purpose of this study was to examine whether intestinal beta-carotene
cleavage activity, measured with the dioxygenase assay, is affected
by vitamin A intake and whether this in vitro activity is a determinant
of beta-carotene cleavage in vivo, measured in lymph-cannulated
rats. Six groups of 10-20 rats were fed a diet with a low, normal
or high retinyl palmitate concentration (120 RE, 1200 RE and
12,000 RE per kg, respectively) for 14 to 18 wk, either supplemented
or not with 50 mg beta-carotene/kg in the last 6 wk. Intestinal
dioxygenase activity was 90% higher (P < 0.05) in the animals
fed the unsupplemented low vitamin A diet than in the animals
fed the unsupplemented high vitamin A diet, whereas in beta-carotene-supplemented
rats intestinal dioxygenase activity was significantly lower
than in unsupplemented rats. The molar ratio between retinyl
esters and beta-carotene in lymph collected over 8 h after a
single intestinal dose of beta-carotene (250 micrograms) to beta-carotene-unsupplemented
rats fed the three levels of vitamin A was correlated with intestinal
dioxygenase activity (r = 0.66, P = 0.003). Dioxygenase activity
in the liver was not affected by the vitamin A concentration
of the diet but was 70% higher in the beta-carotene-supplemented
rats. Based on the difference in liver vitamin A contents between
beta-carotene-supplemented and unsupplemented rats we estimated
beta-carotene conversion factors of 9:1 for the rats fed the
high vitamin A diet and 4:1 for the rats fed the normal and low
vitamin A diets. Intestinal beta-carotene cleavage activity is
higher in vitamin A-deficient rats than in rats with a high intake
of either vitamin A or beta-carotene. The intestinal dioxygenase
activity as measured in vitro is an adequate indicator of in
vivo beta-carotene cleavage activity.
Title
Bioavailability of a natural isomer mixture compared with synthetic
all-trans beta-carotene in human serum.
Author
Ben-Amotz A; Levy Y
Address
National Institute of Oceanography, Israel Oceanographic and
Limnological Research, Haifa.
Source
Am J Clin Nutr, 63(5):729-34 1996 May
Abstract
The unicellular alga Dunaliella bardawil was shown previously
to contain very high concentrations of beta-carotene composed
of about equal amounts of the all-trans and 9-cis isomers, which
differ in their physicochemical features and antioxidative activity.
The uptake of alpha- and beta-carotenes, oxycarotenoids, and
other lipophilic substances from a basal diet supplemented with
synthetic beta-carotene or dry D. bardawil power was studied
in humans. Subjects were given a basal diet supplemented daily
with 40 mg beta-carotene, synthetic or natural, for a relatively
short period of 14 d. Serum analyses at the end of this period
detected mainly oxycarotenoids, and to a lesser extent all-trans
beta-carotene and alpha-carotene, but not 9-cis beta-carotene.
Retinol was increased by the all-trans beta-carotene diet. A
high amount of oxidized dienic, lipophilic polar products was
exhibited in HPLC predominantly in sera from the placebo and
synthetic all-trans beta-carotene groups by strong, short ultraviolet
absorbance peaks of 232 nm. The preferential serum absorption
of all-trans beta-carotene over 9-cis beta-carotene, in parallel
with the appearance of a high concentration of oxidized dienic
products with supplementation of the basal diet with all-trans
beta-carotene compared with the low concentration of serum-oxidized
dienic products with supplementation with a natural beta-carotene
Source, suggests that 9-cis beta-carotene acts as an in
vivo lipophilic antioxidant more efficiently than does all-trans
beta-carotene.
Title
Effect of beta-carotene supplementation on the concentrations
and distribution of carotenoids, vitamin E, vitamin A, and cholesterol
in plasma lipoprotein and non-lipoprotein fractions in healthy
older women.
Author
Ribaya-Mercado JD; Ordovas JM; Russell RM
Address
Jean Mayer US Department of Agriculture Human Nutrition Research
Center on Aging, Tufts University, Boston, MA 02111, USA.
Source
J Am Coll Nutr, 14(6):614-20 1995 Dec
Abstract
OBJECTIVE: We studied the effect of beta-carotene supplementation
on the concentrations and distribution in plasma lipoprotein
and non-lipoprotein fractions of carotenoids, alpha-tocopherol,
retinol, and cholesterol. METHODS: Ten women ingested either
90 mg of beta-carotene or placebo daily for 3 weeks while residing
in their homes and eating their usual meals. Carotenoids (beta-carotene,
lycopene, lutein/zeaxanthin), retinol, alpha-tocopherol, and
cholesterol were measured in plasma lipoprotein and non-lipoprotein
fractions before and after treatment. RESULTS: In the beta-carotene-supplemented
group, total plasma beta-carotene increased 14-fold from 0.48
+/- 0.13 to 6.83 +/- 2.12 mumol/L (p = 0.04). Although the greatest
increase in beta-carotene was in low-density-lipoproteins (LDL),
the magnitude of increase was similar in LDL, high-density-lipoproteins
(HDL), and very-low-density-lipoproteins (VLDL). Thus, the relative
distribution of beta-carotene in lipoproteins was unchanged:
approximately 71% was in LDL, approximately 15% in HDL and approximately
12% in VLDL, before and after beta-carotene supplementation.
There were no changes in amounts and distribution in lipoproteins
of the other carotenoids, alpha-tocopherol, and cholesterol.
There was no change in the amount of retinol in lipoprotein-deficient
plasma. There were no changes in total plasma triglycerides.
Significant positive correlations were found between LDL- or
VLDL-cholesterol and alpha-tocopherol in LDL or VLDL, respectively;
between LDL- or VLDL-cholesterol and lutein/zeaxanthin in LDL
or VLDL, respectively; and between HDL-cholesterol and beta-carotene
in HDL. CONCLUSIONS: beta-Carotene supplementation (90 mg/day
for 3 weeks) in healthy older women results in an enrichment
of all plasma lipoprotein fractions with beta-carotene, but does
not alter the relative distribution of beta-carotene in lipoproteins.
beta-Carotene supplementation has no effect on the amounts and
relative distribution of lycopene, lutein/zeaxanthin, and alpha-tocopherol
in lipoproteins, or of retinol in the non-lipoprotein fraction
of plasma. Short-term beta-carotene supplementation has no effect
on the concentrations of plasma total triglycerides, total cholesterol,
HDL-, LDL-, and VLDL-cholesterol.
Title
Dietary beta-carotene elevates plasma steady-state and tissue
concentrations of beta-carotene and enhances vitamin A balance
in preruminant calves.
Author
Hoppe PP; Chew BP; Safer A; Stegemann I; Biesalski HK
Address
Animal Nutrition Research Station, BASF Aktiengesellschaft, Offenbach,
Germany.
Source
J Nutr, 126(1):202-8 1996 Jan
Abstract
Preruminant calves are regarded as a model for studying beta-carotene
bioavailability in humans. The objectives of this trial were
to determine the relationship between multiple beta-carotene
doses and plasma steady-state concentration, accumulation in
selected tissues, and vitamin A balance in liver. Seventy newborn
Holstein calves in six treatments (n = 10/treatment) were fed
a complete milk replacer diet low in vitamin A and supplemented
with beta-carotene doses of 0, 0.23, 0.46, 0.92, 1.84 or 3.68
mumol/(kg body wt.d) for 28 d. Ten calves were killed on d 1.
Plasma beta-carotene increased in relation to log transformations
of dose and time (P < 0.05) in all supplemented calves and
steady state was attained after 4 wk. For doses up to 0.92 mumol/(kg
body wt.d), the dose-response relationship was linear. A dose-dependent
accumulation of beta-carotene was found for liver, heart, lungs,
adrenals and adipose tissue. All-trans-beta-carotene was the
only isomer in plasma and adrenals and the predominant isomer
in the remaining tissues. In liver, vitamin A increased with
beta-carotene uptake. Hepatic balance between vitamin A accumulation
and loss was achieved at beta-carotene intake of 0.36 mumol/(kg
body wt.d) for a calf of 45 kg. It is concluded that preruminant
calves within 1 mo of age utilize beta-carotene as a Source
of vitamin A, and that for testing bioavailability of beta-carotene
sources, doses up to 0.92 mumol beta-carotene/(kg body wt.d)
are most appropriate.
Title
beta-carotene as a high-potency antioxidant to prevent the formation
of phospholipid hydroperoxides in red blood cells of mice.
Author
Nakagawa K; Fujimoto K; Miyazawa T
Address Department of Applied Biological Chemistry, Tohoku
University, Sendai, Japan. Biochim Biophys Acta, 1299(1):110-6
1996 Jan 5
Abstract
In order to investigate the antioxidant effect of beta-carotene
in vivo, phospholipid hydroperoxides and beta-carotene isomers
in red blood cells (RBC), plasma and tissue organelles were quantitatively
measured after the oral administration of beta-carotene (94.8%
all-trans-beta-carotene) to mice. Three groups of 24 mice each
were fed for 1 week on a semisynthetic diet supplemented with
either 0.6% or 3.0% beta-carotene/diet or maintained on a control
(beta-carotene-unsupplemented) diet. The RBC phospholipid hydroperoxides
showed a significant decrease followed by an increase of beta-carotene
intakes; i.e., 201, 16 and 4 pmol of phosphatidylcholine hydroperoxide/ml
packed RBC, and 108, 22 and 8 pmol of phosphatidylethanolamine
hydroperoxide/ml packed RBC, in the mice given the control diet,
0.6% carotene diet and 3.0% carotene diet, respectively. The
RBC beta-carotene increased from 14 to 43 pmol/ml packed RBC
as followed by the increase of beta-carotene intakes. Such a
potent antioxidant effect of beta-carotene as observed in RBC
was not confirmed in the plasma, liver or lungs, although their
beta-carotene contents increased. The beta-carotene ingestion
increased the all-trans-beta-carotene and retinol contents in
RBC, plasma, liver and lungs, but the alpha-tocopherol content
decreased. In the beta-carotene-supplemented (6 g and 30 g/kg
diet) mice, cis-beta-carotene content was relatively higher in
the RBC (25-35% of total beta-carotene) than that in the plasma,
liver and lungs. The present findings indicate that not only
does beta-carotene act as a potent antioxidant in vivo but also
its antioxidant effect is very specific in the RBC phospholipid
bilayers rather than in the plasma and other tissue organelles.
Title
Effect of beta-carotene supplementation on indices of colonic
cell proliferation.
Author
Frommel TO; Mobarhan S; Doria M; Halline AG; Luk GD; Bowen PE;
Candel A; Liao Y
Address
Department of Medicine, Loyola University Medical Center, Maywood,
IL 60153, USA.
Source
J Natl Cancer Inst, 87(23):1781-7 1995 Dec 6
Abstract
BACKGROUND: Epidemiologic studies have shown that consuming foods
containing beta-carotene is associated with a decreased incidence
of colon cancer. The validity of this association has recently
been questioned. It is not known if the rate of colonic cell
proliferation differs among individuals with or without a history
of colonic polyps or cancer and if proliferation changes in response
to beta-carotene. PURPOSE: This study was intended to (a) determine
whether differences exist in colonic cell proliferation in individuals
with and without prior colonic polyps or tumors, (b) demonstrate
that beta-carotene accumulates in colonic mucosa following dietary
supplementation, and (c) determine whether mucosal beta-carotene
accumulation influences colonic cell proliferation. METHODS:
Subjects were enrolled in the phase I study from June 1991 until
February 1994. The participants included 20 individuals (11 males
and nine females, aged 62.3 +/- 8.9 years [means +/- SD]) with
normal colons (as judged by recent colonoscopy), 40 (24 males
and 16 females, aged 59.6 +/- 10.1 years) with a history of colonic
polyp(s), and 41 (30 males and 11 females, aged 67.2 +/- 9.7
years) with prior colon cancer. The subjects in the last two
groups consumed either 30 mg of beta-carotene or placebo each
morning for 3 months. This dose of beta-carotene has no known
toxic effects, but it can increase the serum level by approximately
10-fold. beta-carotene concentration in serum and colonic tissue
was quantitated by high-pressure liquid chromatography in samples
collected before and after supplementation with beta-carotene
or placebo. Cellular proliferation was assessed on the basis
of tissue ornithine decarboxylase activity, urinary polyamine
excretion, and proliferating cell nuclear antigen expression.
The differences in colonic cell proliferation parameters due
to beta-carotene supplementation, within and among different
groups, were evaluated by the Wilcoxon matched-pairs signed ranked
test and the Mann-Whitney test, respectively. All statistical
tests were two-sided. RESULTS: Colonic cell proliferation did
not differ in samples obtained from individuals with and without
prior colonic polyp(s) or cancer. beta-carotene concentrations
in serum and colonic tissue were significantly increased in groups
receiving beta-carotene (P < .001). However, cell proliferation
did not differ, as judged by any of the three measures, among
samples from all experimental groups collected before and after
supplementation with beta-carotene. CONCLUSIONS: Dietary supplementation
with beta-carotene for a period of 3 months does not alter colonic
cell proliferation in individuals with a history of colonic polyps
or cancer. IMPLICATIONS: The mechanism by which beta-carotene
might reduce colon cancer incidence does not appear to involve
or result in a change in cell proliferation in the normal colonic
mucosa as studied in individuals with a history of colonic polyps
or cancer.
Title
Compartmental analysis of the dynamics of beta-carotene metabolism
in an adult volunteer.
Author
Novotny JA; Dueker SR; Zech LA; Clifford AJ
Address
Department of Nutrition, University of California, Davis 95616,
USA.
Source
J Lipid Res, 36(8):1825-38 1995 Aug
Abstract
Metabolism of a 73 mumol oral dose of beta-carotene-d8 in olive
oil was determined from plasma beta-carotene-d8 and retinol-d4
concentration-time curves in an adult male. beta-Carotene-d8
and retinol-d4 concentrations in serial plasma were measured
using high performance liquid chromatography (HPLC) and gas chromatography-mass
spectrometry (GC-MS), respectively. Plasma beta-carotene-d8 and
retinol-d4 concentration-time curves were described by a 5-term
and a 3-term polyexponential equation, respectively, using an
empirical description of beta-carotene metabolism. A physiologic
compartmental model of beta-carotene metabolism was also constructed
and tested. This model suggests that 22% of the beta-carotene
dose is absorbed: 17.8% as intact beta-carotene and 4.2% as retinoid.
Also, it suggests that both liver and enterocyte are important
in converting beta-carotene to retinoid; 43% is converted in
liver and 57% in enterocyte. Finally, it suggests that the mean
residence time for beta-carotene is 51 days and that the 73 mumole
dose does not alter the fractional transfer coefficients of the
system after absorption takes place. The issue of central versus
eccentric cleavage of beta-carotene in humans can be studied
with further modeling combined with use of appropriately labeled
beta-carotene. |
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