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Science Index

Beta Carotene

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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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