Beta-carotene Supplementation Research Articles

Effects of β-carotene supplementation on chick growth, immune status and behaviour in the grey partridge, Perdix perdix

Carotenoids are important for various functions during chick development. Since these pigments cannot be synthesized, they can be considered limited resources that the mother optimally allocates between herself and her offspring (maternal effect). Some studies have examined the effects of carotenoids on growth and immune function but little is known about their role in behaviour. In this study of the grey partridge, we conducted two supplementation experiments: (1) laying females were fed with beta-carotene enriched or impoverished diets; (2) chicks were fed directly with beta-carotene enriched or impoverished diets. We then evaluated the effects of this carotenoid on chick growth, immunocompetence and anti-predator behaviour (reactions to a raptor model). In the first experiment, the beta-carotene enriched diet given to mothers did not cause any difference in chick physiology. In the second experiment, beta-carotene supplementation of chicks had a significant beneficial effect on their growth and immune response, although their behavioural reactions did not differ in relation to the diet. Therefore, beta-carotene supplementation had beneficial effects on growth and immunocompetence only when directly supplied to chicks. The beneficial effect reported in other species for begging or pecking behaviours was not confirmed for the anti-predator behaviour of grey partridge chicks.

Chemoprevention of gastric cancer

Gastric cancer is the second commonest cause of cancer-associated death in the world. The high mortality is largely attributed to the huge number of at-risk individuals as well as the delay in presentation. Hence, chemoprevention of gastric cancer appears to be the most promising approach in reducing the incidence and mortality related to this cancer. Among various chemoprevention strategies, Helicobacter pylori eradication is the one being most extensively examined. Results from several large-scale prospective randomized studies, however, showed marginal benefits of H. pylori eradication on regression of premalignant gastric lesions. Moreover, there is no significant reduction in gastric cancer incidence. Similarly, ascorbic acid and/or beta-carotene supplementation have borderline effects on premalignant gastric lesions. Based on epidemiological data, the use of non-steroidal anti-inflammatory drugs is associated with a reduced risk of stomach cancer. Future studies should evaluate the role of other chemopreventive agents, particularly specific cyclooxygenase-2 inhibitors, in reducing the risk of gastric cancer.

Cardiovascular disease and Alzheimer's disease: common links

Growing evidence supports a strong and likely causal association between cardiovascular disease (CVD), and its risk factors, with incidence of cognitive decline and Alzheimer's disease. Individuals with subclinical CVD are at higher risk for dementia and Alzheimer's. Several cardiovascular risk factors are also risk factors for dementia, including hypertension, high LDL cholesterol, low HDL cholesterol and especially diabetes. Moderate alcohol appears to be protective for both CVD and dementia. In contrast, inflammatory markers predict cardiovascular risk, but not dementia, despite biological plausibility for such a link. The substantial overlap in risk factors points to new avenues for research and prevention.

The total antioxidant capacity of the diet is an independent predictor of plasma β-carotene

To investigate the contribution of the total antioxidant capacity (TAC) of the diet to plasma concentrations of beta-carotene. Cross-sectional study. Department of Public Health and Department of Internal Medicine and Biomedical Sciences, University of Parma. A total of 247 apparently healthy adult men (n=140) and women (n=107). A medical history, a physical exam including height, weight, waist circumference and blood pressure measurements, a fasting blood draw, an oral glucose tolerance test and a 3-day food record. We observe a negative trend across quartiles of plasma beta-carotene for most biological variables clustering in the insulin resistance syndrome, as well as for traditional and new risk factors for type II diabetes and cardiovascular disease (CVD), including C-reactive protein and gamma-glutamyltranspeptidase (P<0.05). Regarding dietary characteristics, energy-adjusted intake of fat, fiber, fruits, vegetables, beta-carotene, vitamin C, vitamin E and dietary TAC significantly increased with increasing plasma beta-carotene (P<0.05), whereas alcohol intake decreased (P=0.013). Adjusted geometric means (95% confidence interval) of plasma beta-carotene significantly increased across quartiles of dietary TAC, even when single dietary antioxidants were considered in the model (QI=0.087 mg/dl (0.073-0.102); QII=0.087 mg/dl (0.075-0.103); QIII=0.114 mg/dl (0.098-0.132) and QIV=0.110 mg/dl (0.093-0.130); P for linear trend=0.026). When the population was divided on the basis of alcohol consumption, this trend was also observed in subjects drinking <20 g alcohol/day (P=0.034), but not in those with higher alcohol intake (P=0.448). Dietary TAC is an independent predictor of plasma beta-carotene, especially in moderate alcohol drinkers. This may explain, at least in part, the inverse relationship observed between plasma beta-carotene and risk of chronic diseases associated to high levels of oxidative stress (i.e., diabetes and CVD), as well as the failure of beta-carotene supplements alone in reducing such risk.

Effect of dietary antioxidants and risk of oral, pharyngeal and laryngeal squamous cell carcinoma according to smoking and drinking habits

Several intervention trials and prospective studies have reported that beta-carotene supplementation is not associated with a decreased risk of several cancers among smokers and drinkers, and that it may even have adverse effects in these groups. The relationship between dietary antioxidant intake and the risk of head and neck squamous cell carcinoma (HNSCC) has been examined intensively, but little is known about the effects of antioxidants on HNSCC with respect to smoking and drinking habits. Here, we conducted a case-control study of 385 histologically confirmed cases of HNSCC (193 oral, 132 pharyngeal and 60 laryngeal), excluding nasal and paranasal cancer, and 1925 age-matched and sex-matched cancer-free outpatient controls using data from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center, Japan. The intake of nutrients and food groups was assessed with a food frequency questionnaire, and multivariate-adjusted odds ratios for cancer were estimated for smoking and drinking habits using logistic models. The results showed an overall inverse association between the intake of dietary antioxidants, including carotene, and vitamins C and E, and risk of HNSCC. The protective effect of these antioxidants was seen in both men and women. High consumption of antioxidants was associated with a decreased risk of HNSCC among smokers, drinkers and those with both smoking and drinking habits. These findings suggest that dietary antioxidant intake prevents HNSCC in smokers and drinkers.

Supplemental and Dietary Vitamin E, β-Carotene, and Vitamin C Intakes and Prostate Cancer Risk

Vitamin E, beta-carotene, and vitamin C are micronutrient antioxidants that protect cells from oxidative damage involved in prostate carcinogenesis. In separate trials, supplemental vitamin E was associated with a decreased risk of prostate cancer among smokers and supplemental beta-carotene was associated with a decreased risk of prostate cancer among men with low baseline plasma beta-carotene levels. We evaluated the association between intake of these micronutrient antioxidants from foods and supplements and the risk of prostate cancer among men in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. At baseline, trial participants completed a 137-item food frequency questionnaire that included detailed questions on 12 individual supplements. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. We identified 1338 cases of prostate cancer among 29 361 men during up to 8 years of follow-up. Overall, there was no association between prostate cancer risk and dietary or supplemental intake of vitamin E, beta-carotene, or vitamin C. However, among current and recent (i.e., within the previous 10 years) smokers, decreasing risks of advanced prostate cancer (i.e., Gleason score > or = 7 or stage III or IV) were associated with increasing dose (RR for > 400 IU/day versus none = 0.29, 95% CI = 0.12 to 0.68; Ptrend = .01) and duration (RR for > or = 10 years of use versus none = 0.30, 95% CI = 0.09 to 0.96; Ptrend = .01) of supplemental vitamin E use. Supplemental beta-carotene intake at a dose level of at least 2000 microg/day was associated with decreased prostate cancer risk in men with low (below the median of 4129 microg/day) dietary beta-carotene intake (RR = 0.52, 95% CI = 0.33 to 0.81). Among smokers, the age-adjusted rate of advanced prostate cancer was 492 per 100,000 person-years in those who did not take supplemental vitamin E, 153 per 100,000 person-years in those who took more than 400 IU/day of supplemental vitamin E, and 157 per 100,000 person-years in those who took supplemental vitamin E for 10 or more years. Among men with low dietary beta-carotene intake, the age-adjusted rate of prostate cancer was 1122 per 100,000 person-years in those who did not take supplemental beta-carotene, and 623 per 100,000 person-years in those who took at least 2000 microg/day of supplemental beta-carotene. Our results do not provide strong support for population-wide implementation of high-dose antioxidant supplementation for the prevention of prostate cancer. However, vitamin E supplementation in male smokers and beta-carotene supplementation in men with low dietary beta-carotene intakes were associated with reduced risk of this disease.

β-Carotene breakdown products enhance genotoxic effects of oxidative stress in primary rat hepatocytes

Since it has to be expected that individuals exposed to oxidative stress who take supplements of beta-carotene are simultaneously exposed to both beta-carotene cleavage products (CPs) and oxidative stress, and both exposures have been demonstrated to cause genotoxic effects in primary rat hepatocytes, cyto- and genotoxic effects on primary rat hepatocytes after supplementation of the medium with increasing concentrations of a CP mixture during exposure to oxidative stress by treatment with either DMNQ (2,3-dimethoxy-1,4-naphthoquinone) or hypoxia/reoxygenation (Hy/Reox) was investigated. The cytological endpoints analysed were the mitotic indices, the percentages of apoptotic and necrotic cells, the percentages of micronucleated (MN) cells and the number of chromosomal aberrations (CAs) and sister chromatid exchanges (SCE). The results obtained clearly demonstrate that the CP mixture enhances the genotoxic effects of oxidative stress exposure, whereas it had no effect at all on the endpoints of cytotoxicity studied. These results further support the hypothesis that CP might be responsible for the reported carcinogenic response in the beta-CArotene and Retinol Efficacy Trial (CARET) and Alpha-Tocopherol Beta-carotene Cancer prevention (ATBC) chemoprevention trials.

Combined antioxidant (β-carotene, α-tocopherol and ascorbic acid) supplementation increases the levels of lung retinoic acid and inhibits the activation of mitogen-activated protein kinase in the ferret lung cancer model

Interactions among beta-carotene (BC), alpha-tocopherol (AT) and ascorbic acid (AA) led to the hypothesis that using a combination of these antioxidants could be more beneficial than using a single antioxidant alone, particularly against smoke-related lung cancer. In this investigation, we have conducted an animal study to determine whether combined BC, AT and AA supplementation (AOX) protects against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis in smoke-exposed (SM) ferrets. Ferrets were treated for 6 months in the following four groups: (i) control, (ii) SM + NNK, (iii) AOX and (iv) SM + NNK + AOX. Results showed that the combined AOX supplementation (i) prevented the SM + NNK-decreased lung concentrations of retinoic acid (RA) and BC; (ii) inhibited the SM + NNK-induced phosphorylation of Jun N-terminal kinase (JNK), extracellular-signal-regulated protein kinase (ERK) and proliferating cellular nuclear antigen proteins in the lungs of ferrets; and (iii) blocked the SM + NNK-induced up-regulation of total p53 and Bax proteins, as well as phosphorylated p53 in the lungs of ferrets. In addition, there were no lesions observed in the lung tissue of ferrets in the control and/or the AOX groups after 6 months of intervention, but combined AOX supplementation resulted in a trend toward lower incidence of both preneoplastic lung lesions and lung tumor formation in SM + NNK + AOX group of ferrets, as compared with the SM + NNK group alone. These data indicate that combined AOX supplementation could be a useful chemopreventive strategy against lung carcinogenesis through maintaining normal tissue levels of RA and inhibiting the activation of mitogen-activated protein kinase pathways, cell proliferation and phosphorylation of p53.

Eat your fruit and vegetables

Your parents were smart when they told you to eat all of your vegetables, and encouraged you to eat your fruit, but they probably did not know that eating more fruit and vegetables would lower the risk of stroke. 1 He FJ Nowson CA MacGregor GA Fruit and vegetable consumption and stroke: a meta-analysis of cohort studies. Lancet. 2006; 367: 320-326 Summary Full Text Full Text PDF PubMed Scopus (792) Google Scholar , 2 Ness AR Maynard M Frankel S et al. Diet in childhood and adult cardiovascular and all cause mortality: the Boyd Orr cohort. Heart. 2005; 91: 894-898 Crossref PubMed Scopus (135) Google Scholar Results of epidemiological studies of the relation between intakes of nutrients in fruit and vegetables, such as vitamin C or beta-carotene, and risk of stroke have been inconsistent. 3 Ness AR Powles JW Fruit and vegetables, and cardiovascular disease: a review. Int J Epidemiol. 1997; 26: 1-13 Crossref PubMed Scopus (1083) Google Scholar , 4 Leppala JM Virtamo J Fogelholm R et al. Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers. Arterioscler Thromb Vasc Biol. 2000; 20: 230-235 Crossref PubMed Scopus (158) Google Scholar However, disease prevention might not be attributable to single nutrients, but to the interaction of nutrient and non-nutritive components in whole foods. Fruit and vegetables are rich in many health-promoting nutrients and food compounds, including antioxidants such as vitamin C and folate, potassium, phytochemicals, dietary fibre, and plant proteins that have been inversely related to high blood pressure and stroke. 3 Ness AR Powles JW Fruit and vegetables, and cardiovascular disease: a review. Int J Epidemiol. 1997; 26: 1-13 Crossref PubMed Scopus (1083) Google Scholar , 4 Leppala JM Virtamo J Fogelholm R et al. Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers. Arterioscler Thromb Vasc Biol. 2000; 20: 230-235 Crossref PubMed Scopus (158) Google Scholar , 5 Appel LJ Moore TJ Obarzanek E et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. 1997; 336: 1117-1124 Crossref PubMed Scopus (4242) Google Scholar , 6 Steffen LM Kroenke CH Yu X et al. Associations of plant foods, dairy products, and meat consumption with fifteen-year incidence of elevated blood pressure in young black and white adults: The CARDIA Study. Am J Clin Nutr. 2005; 82: 1169-1177 PubMed Google Scholar , 7 John JH Ziebland S Yudkin P Roe LS Neil HA for the Oxford Fruit and Vegetable Study GroupEffects of fruit and vegetable consumption on plasma antioxidant concentrations and blood pressure: a randomised controlled trial. Lancet. 2002; 359: 1969-1974 Summary Full Text Full Text PDF PubMed Scopus (405) Google Scholar , 8 Bazzano LA He J Ogden LG et al. Dietary intake of folate and risk of stroke in US men and women: NHANES I epidemiologic follow-up study. National health and nutrition examination survey. Stroke. 2002; 33: 1183-1188 Crossref PubMed Scopus (133) Google Scholar It is likely that the combination of nutrients and compounds in foods has greater health benefits than the individual nutrient alone. 9 Jacobs DR Steffen LM Nutrients, foods, and dietary patterns as exposures in research: a framework for food synergy. Am J Clin Nutr. 2003; 78: 508S-513S PubMed Google Scholar In this week's Lancet, a meta-analysis by Feng He and colleagues provides strong evidence of an inverse relation between fruit and vegetable intake and risk of stroke. 1 He FJ Nowson CA MacGregor GA Fruit and vegetable consumption and stroke: a meta-analysis of cohort studies. Lancet. 2006; 367: 320-326 Summary Full Text Full Text PDF PubMed Scopus (792) Google Scholar Compared with individuals who consumed less than 3 servings of fruit and vegetables per day, those who ate more than 5 daily servings of fruit and vegetables had a 26% lower risk of stroke, while 3–5 servings per day conferred a 9% lower risk. Less than a quarter of adults in the USA eat 5 or more servings of fruit and vegetables per day, and there is therefore a serious need to develop and implement public-health strategies to achieve this dietary goal. Fruit and vegetable consumption and stroke: meta-analysis of cohort studiesIncreased fruit and vegetable intake in the range commonly consumed is associated with a reduced risk of stroke. Our results provide strong support for the recommendations to consume more than five servings of fruit and vegetables per day, which is likely to cause a major reduction in strokes. Full-Text PDF

Effects of quercetin and β‐carotene supplementation on azoxymethane‐induced colon carcinogenesis and inflammatory responses in rats fed with high‐fat diet rich in ω‐6 fatty acids

Chronic inflammation in gastrointestinal tract has been suggested as a risk factor for tumor formation. The effect of dietary supplementation of quercetin or beta-carotene on colon carcinogenesis and inflammatory response in rats fed with high-fat diet rich in omega-6 fatty acids was assessed. Animals were exposed to two weekly subcutaneous injections of AOM (azoxymethane) at a single dose of 15 mg/kg body weight. A portion of rats from each group was sacrificed at 8 weeks after the last AOM treatment to determine ACF (aberrant crypt foci) formation. Colonic mucosa expression of iNOS (inducible nitric oxide) and COX-2 (cyclooxygenase-2) protein, and blood PGE2 (prostaglandin E2) level were measured. The remaining groups of animals were sacrificed at 33 weeks after the last AOM treatment to examine colon tumor formation. Rats on high-fat diet developed more aberrant crypt foci (P<0.05) compared with those of rats on regular diet. In the same vein, but in contrast to the effect seen with regular diet, the high-fat diet induced a significant up-regulation of iNOS expression. There was no significant change in the extent of COX-2 expression or in the PGE2 levels. Quercetin or beta-carotene supplementation reduced the number of ACF only in animals fed high-fat diet (p<0.05), however, no significant difference in tumor incidence was found. At week 33, the expression of iNOS was reduced by quercetin without a statistical significance, and COX-2 expression was slightly reduced in rats on beta-carotene supplementation. No change in PGE2 levels was observed. Whilst dietary antioxidants are considered as effective suppressors for precancerous lesion formation in colons exposed to high-risk diet, it is clear that elucidating the role of individual antioxidants in colon tumor formation coupled with an understanding of the molecular mechanisms involved would benefit colon cancer prevention strategies.

Dietary β-carotene inhibits mammary carcinogenesis in rats depending on dietary α-linolenic acid content

To investigate whether dietary alpha-linolenic acid (ALA) content alters the effect of beta-carotene on mammary carcinogenesis, we conducted a chemically induced mammary tumorigenesis experiment in rats randomly assigned to four nutritional groups (15 rats per group) varying in beta-carotene supplementation and ALA content. Two oil formula-enriched diets (15 %) were used: one with 6 g ALA/kg diet in an essential fatty acids (EFA) ratio of linoleic acid:ALA of 5:1 w/w (EFA 5 diet), the other with 24 g ALA/kg diet in an EFA ratio of 1:1 w/w (EFA 1 diet), both designed with a similar linoleic acid content. beta-Carotene was either added (10 mg/kg diet per d) or not added to these diets. beta-Carotene supplementation led to decreased tumour incidence and tumour growth when added to the EFA 5 diet, whereas it had no effect when added to the EFA 1 diet. The decreased tumour growth did not result from an involvement of lipoperoxidation (tumour malondialdehyde content being similar between the groups) or from an inhibition of tumour cell proliferation (as there was an unchanged S phase fraction in the tumours). We concluded that an adequate content of ALA in the diet is required to allow a protective effect of beta-carotene in mammary carcinogenesis. Whether such an interaction between ALA and beta-carotene influences the risk of breast cancer in women needs to be investigated.

Beta-Carotene Supplementation Attenuates Cardiac Remodeling Induced by One-Month Tobacco-Smoke Exposure in Rats

The objectives were to analyze the cardiac effects of exposure to tobacco smoke (ETS), for a period of 30 days, alone and in combination with beta-carotene supplementation (BC). Rats were allocated into: Air (control, n = 13); Air + BC (n = 11); ETS (n = 11); and BC + ETS (n = 9). In Air + BC and BC + ETS, 500 mg of BC were added to the diet. After three months of randomization, cardiac structure and function were assessed by echocardiogram. After that, animals were euthanized and morphological data were analyzed post-mortem. One-way and two-way ANOVA were used to assess the effects of ETS, BC and the interaction between ETS and BC on the variables. ETS presented smaller cardiac output (0.087 +/- 0.001 vs. 0.105 +/- 0.004 l/min; p = 0.007), higher left ventricular diastolic diameter (19.6 +/- 0.5 vs. 18.0 +/- 0.5 mm/kg; p = 0.024), higher left ventricular (2.02 +/- 0.05 vs. 1.70 +/- 0.03 g/kg; p < 0.001) and atrium (0.24 +/- 0.01 vs. 0.19 +/- 0.01 g/kg; p = 0.003) weight, adjusted to body weight of animals, and higher values of hepatic lipid hydroperoxide (5.32 +/- 0.1 vs. 4.84 +/- 0.1 nmol/g tissue; p = 0.031) than Air. However, considering those variables, there were no differences between Air and BC + ETS (0.099 +/- 0.004 l/min; 19.0 +/- 0.5 mm/kg; 1.83 +/- 0.04 g/kg; 0.19 +/- 0.01 g/kg; 4.88 +/- 0.1 nmol/g tissue, respectively; p > 0.05). Ultrastructural alterations were found in ETS: disorganization or loss of myofilaments, plasmatic membrane infolding, sarcoplasm reticulum dilatation, polymorphic mitochondria with swelling and decreased cristae. In BC + ETS, most fibers showed normal morphological aspects. One-month tobacco-smoke exposure induces functional and morphological cardiac alterations and BC supplementation attenuates this ventricular remodeling process.

Prescription versus herbal medications for prostate cancer prevention: Why history cannot be allowed to repeat itself in your clinical practice

It is obvious that herbal dietary supplements have enjoyed a great deal of popularity and sales throughout the past decade and, in the area of prostate cancer prevention, this is especially the case. However, the lack of currently available evidence to indicate their effectiveness truly is a potential problem. In addition, the quality control, safety, and regulatory issues abound. However, regardless of this, one only needs to point toward the history of specific supplements for the prevention and treatment of cancer throughout the past 30 years to realize that there indeed is reason for concern. Beta-carotene supplements, shark cartilage, PC-SPES, vitamin C, and zinc are just a few examples of why clinicians cannot let history repeat itself. In other words, until the results of large randomized trials are published, the best course of action may be promoting no action at all. Lifestyle changes, supplements, and prescription medications that promote overall heart health for patients who qualify seem to make the most sense at this time because even in the worst-case scenario, patients still benefit. Most of the herbal medications that seem promising (eg, flaxseed) have been studied mostly using the dietary, not the supplement form, and this has to be emphasized to patients. The herbal prostate health supplements such as saw palmetto, pygeum, stinging nettle, and others have no adequate clinical data to suggest any impact on cancer prevention. However, their use by individuals at screening sites increases the probability that history may unfortunately repeat itself.

Twice the Amount of α-Carotene Isolated from Carrots Is as Effective as β-Carotene in Maintaining the Vitamin A Status of Mongolian Gerbils

The vitamin A (VA) value of carotenoids from fruits and vegetables is affected by many factors. This study determined the VA value of alpha-carotene isolated from carrots compared with beta-carotene and retinyl acetate supplements fed to Mongolian gerbils (Meriones unguiculatus). Gerbils (n = 38) were fed a VA-free diet for 4 wk. At baseline, 6 gerbils were killed to determine liver VA. Gerbils were divided into 3 treatment groups (n = 9/group) and given 35, 35, or 17.5 nmol retinyl acetate, alpha-carotene or beta-carotene, respectively, in 2 divided doses 5 h apart each day. The remaining 5 gerbils received oil vehicle. Gerbils were killed after 3 wk of supplementation. Serum samples and livers were collected and analyzed for VA. Liver extracts were subsequently saponified to quantify alpha-retinol. Serum retinol concentrations did not differ among the groups. Liver retinyl palmitate concentrations were significantly higher in the retinyl acetate treatment group (0.198 +/- 0.051 micromol/g; P < 0.05) than in all other groups. The alpha- and beta-carotene treatments resulted in similar retinyl palmitate concentrations, i.e., 0.110 +/- 0.026 and 0.109 +/- 0.051 micromol/g, respectively, which did not differ from the concentrations in gerbils killed at baseline (0.123 +/- 0.024 micromol/g). The oil group had significantly less retinyl palmitate (0.061 +/- 0.029 micromol/g; P < 0.05) than all other groups. alpha-Retinol was detected in livers of the alpha-carotene group (0.062 +/- 0.013 micromol/g). Thus, twice the amount of purified alpha-carotene maintained VA status as well as beta-carotene in VA-depleted gerbils. Conversion factors were approximately 5.5 microg alpha-carotene or approximately 2.8 mug beta-carotene to 1 microg retinol.

Growth stimulation of human pulmonary adenocarcinoma cells and small airway epithelial cells by β-carotene via activation of cAMP, PKA, CREB and ERK1/2

An alpha-tocopherol, beta-carotene supplementation trial (ATBC) and a chemoprevention trial with beta-carotene and retinoids (CARET trial) were conducted in the 1990s in populations at risk for the development of lung cancer. Both trials had to be discontinued due to significant increases in lung cancer and cardiovascular mortality. Clinical trials to test the cancer preventive effects of beta-carotene are still ongoing, and high concentrations of this provitamin are contained in numerous dietary supplements. Using a cell line derived from a human pulmonary adenocarcinoma (PAC) of Clara cell lineage and immortalized human small airway epithelial cells, our data show that low concentrations of beta-carotene that can be realistically expected in human tissues after oral administration caused a significant increase in intracellular cAMP and activated PKA, as well as in phosphorylation of ERK1/2 and CREB. Furthermore, the proliferation of cells was significantly stimulated by identical concentrations of beta-carotene as monitored by MTT assays. Control experiments with retinol also showed stimulation of cell proliferation and activation of PKA in both cell lines. In light of the fact that PAC is the leading type of lung cancer, these findings suggest that the growth promoting effects of beta-carotene on this cancer type observed in our experiments may have contributed to the unfortunate outcome of the ATBC and CARET trials. This interpretation is supported by the fact that elevated levels of cAMP in the cardiovascular system play a major role in the genesis of cardiovascular disease, which was also greatly promoted in the CARET trial. Our data challenge the widely accepted view that beta-carotene may be useful as a cancer preventive agent.

Lycopene induces apoptosis in immortalized fibroblasts exposed to tobacco smoke condensate through arresting cell cycle and down-regulating cyclin D1, pAKT and pBad

There is a lot of interest in the health benefits of dietary carotenoids and on the relationship of these compounds with smoke. In particular, it is unknown if the enhanced cancer risk observed in smokers following beta-carotene supplementation can be also found using other carotenoids. Here, we studied the effects of the tomato carotenoid lycopene on molecular pathways involved in cell cycle progression, apoptosis and survival in immortalized RAT-1 fibroblasts exposed to cigarette smoke condensate (TAR). Lycopene (0.5-2.0 microM) inhibited cell growth in a dose-and time-dependent manner, by arresting cell cycle progression and by promoting apoptosis in cells exposed to TAR. The arrest of cell cycle was independent of p53 and of 8-OH-dG DNA damage and related to a decreased expression of cyclin D1. Moreover, the carotenoid up-regulated apoptosis and down-regulated the phosphorylation of AKT and Bad in cells exposed to TAR. Such an effect was associated to an inhibition of TAR-induced expression of Cox-2 and hsp90, which is known to maintain AKT activity. This study suggests that lycopene, differently from beta-carotene, can exert protective effects against cigarette smoke condensate.

Tobacco Use and Associations of β-Carotene and Vitamin Intakes with Colorectal Adenoma Risk

The effects of vitamins and beta-carotene on the risk of colorectal adenomas have not been fully investigated. Recent data suggest that smoking could modulate the effect of beta-carotene supplements on adenoma recurrence. We investigated the effect of dietary vitamins and beta-carotene on the risk of adenomas, and a potential interaction with smoking status as part of a case-control study of environmental factors associated with the risk of colorectal adenomas and cancers. We compared nutrient intakes in polyp-free controls (n = 427) and adenoma cases (n = 362) globally and using models stratified by smoking status, adjusted for age, sex, BMI, and energy and alcohol intakes. Folate and vitamins C and B-6 were inversely related to adenoma risk (P for trend = 0.005, 0.03, and 0.02, respectively), whereas vitamin D tended to be inversely associated with risk (P for trend = 0.05). There was a significant interaction between beta-carotene and smoking (P interaction = 0.04). In nonsmokers, beta-carotene was inversely associated with adenoma risk, especially that of colon adenomas [odds ratios (ORs) in low vs. high consumers and 95% CI 0.4 (0.2-0.9)], whereas in past or current smokers, beta-carotene was associated with a nonsignificant (P for trend = 0.19) increase in the risk of colon adenomas [corresponding OR = 1.9 (95% CI = 0.9-4.1)]. Our findings support a protective effect of folate and vitamins C and B-6 irrespective of smoking habits, and a protective effect of beta-carotene in nonsmokers only. They suggest an adverse effect of beta-carotene in smokers, who should be cautious about taking high doses of this micronutrient.

Dual Association of β-Carotene With Risk of Tobacco-Related Cancers in a Cohort of French Women

Intervention studies have demonstrated that, in smokers, beta-carotene supplements had a deleterious effect on risk of lung cancer and may have a deleterious effect on digestive cancers as well. We investigated a potential interaction between beta-carotene intake and smoking on the risk of tobacco-related cancers in women. A total of 59,910 women from the French Etude Epidémiologique de Femmes de la Mutuelle Générale de l'Education Nationale (E3N) prospective investigation were studied from 1994. After a median follow-up of 7.4 years, 700 women had developed cancers known to be associated with smoking. Diet, supplement use, and smoking status at baseline were assessed by self-report. beta-carotene intake was classified into four groups: first (low intake), second, and third tertiles of dietary intake, and use of supplements (high intake). Unadjusted and multivariable Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals (CIs) for cancer risk. All statistical tests were two-sided. Among never smokers, multivariable hazard ratios of all smoking-related cancers were 0.72 (95% CI = 0.57 to 0.92), 0.80 (95% CI = 0.64 to 1.01), and 0.44 (95% CI = 0.18 to 1.07) for the second and third tertiles of dietary intake, and high beta-carotene intake, respectively, compared with low intake (Ptrend = .03). Among ever smokers, multivariable hazard ratios were 1.43 (95% CI = 1.05 to 1.96), 1.20 (95% CI = 0.86 to 1.67), and 2.14 (95% CI = 1.16 to 3.97) for the second and third tertiles of dietary intake, and high beta-carotene intake, respectively, compared with low intake (Ptrend = .09). Tests for interaction between beta-carotene intake and smoking were statistically significant (Ptrend =.017). In this population, the absolute rates over 10 years in those with low and high beta-carotene intake were 181.8 and 81.7 cases per 10,000 women in never smokers and 174.0 and 368.3 cases per 10,000 women in ever smokers. beta-carotene intake was inversely associated with risk of tobacco-related cancers among nonsmokers with a statistically significant dose-dependent relationship, whereas high beta-carotene intake was directly associated with risk among smokers.

β-Carotene Attenuates the Paradoxical Effect of Tobacco Smoke on the Mortality of Rats after Experimental Myocardial Infarction

The objective of this study was to investigate the effects of exposure to tobacco smoke (ETS) in rats that were or were not supplemented with dietary beta-carotene (BC), on ventricular remodeling and survival after myocardial infarction (MI). Rats (n = 189) were allocated to 4 groups: the control group, n = 45; group BC administered 500 mg/kg diet, n = 49, BC supplemented rats; group ETS, n = 55, rats exposed to tobacco smoke; and group BC+ETS, n = 40. Wistar rats weighing 100 g were administered one of the treatments until they weighed 200 to 250 g (approximately 5 wk). The ETS rats were exposed to cigarette smoke for 30 min 4 times/d, in a chamber connected to a smoking device. After reaching a weight of 200-250 g, rats were subjected to experimental MI (coronary artery occlusion) and mortality rates were determined over the next 105 d. In addition, echocardiographic, isolated heart, morphometrical, and biochemical studies were performed. Mortality data were tested using Kaplan-Meyer curves and other data by 2-way ANOVA. Survival rates were greater in the ETS group (58.2%) than in the control (33.3%) (P = 0.001) and BC+ETS rats (30.0%) (P = 0.007). The groups did not differ in the other comparisons. Left ventricular end-diastolic diameter normalized to body weight was greater and maximal systolic pressures were lower in the ETS groups than in non-ETS groups. Previous exposure to tobacco smoke induced a process of cardiac remodeling after MI. There is a paradoxical protector effect with tobacco smoke exposure, characterized by lower mortality, which is offset by BC supplementation.

Plasma appearance of labeled β-carotene, lutein, and retinol in humans after consumption of isotopically labeled kale

The bioavailability of carotenoids from kale was investigated by labeling nutrients in kale with 13C, feeding the kale to seven adult volunteers, and analyzing serial plasma samples for labeled lutein, beta-carotene, and retinol. Ingested doses of labeled carotenoids were 34 micromol for beta-carotene and 33 micromol for lutein. Peak plasma concentrations, areas under the plasma concentration-time curves (AUCs), and percentages of dose recovered at peak plasma concentrations were calculated. Average peak plasma concentrations were 0.38, 0.068, and 0.079 microM for [13C]lutein, [13C]beta-carotene, and [13C]retinol, respectively. Average AUC values (over 28 days) were 42.8, 13.6, 13.2 microM h for [13C]lutein, [13C]beta-carotene, and [13C]retinol, respectively. Percentages of dose recovered at peak plasma concentrations were 3.6, 0.7, and 0.7% for [13C]lutein, [13C]beta-carotene, and [13C]retinol, respectively. A positive relationship was observed between baseline plasma retinol levels and [13C]retinol plasma response. It is possible that this relationship was mediated either through some aspect of beta-carotene absorption or via the common pathways of metabolism for postdose and endogenous retinoid.