The vitamin A activity of beta-carotene

In rats (parameters: growth, epithelial protection and liver storage), and in chicks (liver storage), it has been demonstrated that the conversion of beta-carotene to vitamin A diminishes inversely to the intake of beta-carotene, as long as the dosages are higher than 1-2 times the daily requirements. The decrease in the biopotency of beta-carotene follows a Michaelis Menten kinetic. In the dosage range of the daily requirements molecular ratio applies. Based on these findings, the following guidelines for the conversion of retinol in man are proposed: (Table: see text). For beta-carotene in oily solutions, a conversion factor of 1:3.33 should be accepted for the dosage range of 1,500 to 4,000 micrograms. For higher doses, this factor should be decreased according to the results with laboratory animals: For beta-carotene in vegetables, the conversion factor of 1:6.0 should be accepted for intakes between 1,500 and 4,000 micrograms. A higher factor should be chosen for smaller intakes, and a smaller factor for higher intakes.     

Provitamin A function of carotenoids: the conversion of beta-carotene into vitamin A

Two pathways have been suggested for the conversion of carotenoids to vitamin A in mammals, central cleavage and excentric cleavage. An enzyme, beta-carotenoid-15,15'-dioxygenase (EC 1.13.11.21), has been partly purified from the intestines of several species and has been identified in several other organs and species. The enzyme, which converts beta-carotene into two molecules of retinal in good yield, requires molecular oxygen and is inhibited by sulfhydryl-binding and iron-binding reagents. Most provitamin A carotenoids, including the beta-apo-carotenals, are cleaved to retinal by this enzyme. Its maximal activity in the rabbit is approximately 200 times that required to meet nutritional needs but is less than 50% of that expected to produce signs of vitamin A toxicity. Excentric cleavage unquestionably occurs in plants and some microorganisms and might occur in mammals. Thus far, however, carotenoid dioxygenase with excentric bond specificity has been identified in mammals, the yield of beta-apo-carotenals from beta-carotene in vivo and in vitro is very low, and beta-apo-carotenals are formed nonbiologically from beta-carotene. To remain viable as an alternative pathway of vitamin A formation from carotenoids in mammals, the excentric cleavage hypothesis clearly requires unambiguous direct supporting evidence.     

Chemopreventive trials with vitamin A and beta-carotene: some unresolved issues

The administration of beta-carotene (180 mg/week) plus vitamin A (100,000 IU/week) or vitamin A alone (200,000 IU/week) to chewers of betel quids in Kerala, India led to a reduction in the frequency of micronucleated buccal mucosal cells, a remission of oral leukoplakia, and an inhibition of the development of new leukoplakias. The advantages of this test system include a profound knowledge of exposure levels to tobacco-specific nitrosamines, areca nut-specific nitrosamines, and reactive oxygen species (ROS)-generating polyphenolics; the ease of quantitating micronuclei in exfoliated buccal mucosal cells and oral leukoplakia by noninvasive procedures; and solid information on the incidence of preneoplastic lesions and carcinomas. Some practical issues such as the level of nontoxic beta-carotene which could maintain the reduced frequency of micronucleated cells and the remission of oral leukoplakias for prolonged periods of time, the logistics of distributing beta-carotene to the many millions of smokeless tobacco users who are at elevated risk for oral cancer, and the possibility of using beta-carotene in the form of sweet potatoes or red palm oil, which could contain an economical source of beta-carotene for developing countries in which most of the tobacco chewers live, still remain unresolved.     

Dual isotope test for assessing beta-carotene cleavage to vitamin A in humans

Summary. Background: The ability of β-carotene to deliver bioactive retinoids to tissues is highly variable. A clearer understanding of the environmental and genetic factors that modulate the vitamin A potential of β-carotene is needed. Aim of study: Assess the vitamin A value of orally administered β-carotene relative to a co-administered reference dose of preformed vitamin A. Methods: Equimolar doses (30 μmol) of hexadeuterated D₆β-carotene and D₆ retinyl acetate were orally co-administered in an emulsified formulation to a male subject. The plasma concentration time courses of D₆ retinol (derived from D₆ retinyl acetate) and bioderived D₃ retinol (from D₆β-carotene) were determined for 554 h postdosing using gas chromatography/mass spectrometry. Intact D₆β-carotene plasma concentrations were determined by high-pressure liquid chromatography. The ratio of the two forms of vitamin A, D₆ retinol/D₃ retinol, at any single time point is postulated to reflect the quantity of vitamin A derived from β-carotene relative to preformed vitamin A. Additionally, a minute amount of ¹⁴C β-carotene (50 nCi; 0.27 μg) was included in the oral dose and cumulative 24-h stool and urine samples were collected for two weeks to follow absorption and excretion of the b-carotene. The ¹⁴C nuclide was detected using accelerator mass spectrometry (AMS). Results During the absorption/distribution phase (3–11 h) the D₆/D₃ ratio of the two retinols was not stable and ranged between a value of 3 and 16. Between 11 and 98 h postdosing the ratio was relatively stable with a mean value of 8.5 (95 % CI: 7.5, 8.7). These data suggest that in this subject and under these conditions, 8.5 moles of β-carotene would provide a vitamin A quantity equivalent to 1 mole of preformed vitamin A. On a mass basis, 15.9 μg of β-carotene was equivalent to 1 μg of retinol. The total administered β-carotene was found to be 55 % absorbed by AMS analysis of cumulative stool. Conclusion: The co-administration of D₆β-carotene and D₆ retinyl acetate provides a technique for assessing individual ability to process β-carotene to vitamin A. The results indicate that a single time point taken between 11–98 h after dose administration may provide a reliable value for the relative ratio of the two forms of vitamin A. However, results from more subjects are needed to assess the general utility of this method. Received: 29 November 2001, Accepted: 3 June 2002     

Immunomodulation in humans caused by beta-carotene and vitamin A

Carotenoids and retinoids can stimulate some human immune responses. These include cytoine release with anti-tumor cell activity, increased natural killer cells and activated lymphocytes after both in vitro and in vivo treatment with beta carotene. Such stimulations seem only partly due to retinoids formed from carotenoid metabolism and may be due to effects caused by the structure of beta carotene. Changes in immune functions could explain in part the cancer resistance provided by high carotenoid or retinoid intakes in animals.     

Influence of dietary fats and vitamin E on plasma and hepatic vitamin A and beta-carotene levels in rats fed excess beta-carotene

Effects of different dietary lipids and excess vitamin E on plasma and hepatic concentrations of beta-carotene were evaluated in rats fed diets containing a large excess (0.2%) of beta-carotene. Male weanling Wistar Kyoto rats were fed beta-carotene-supplemented diets containing various dietary lipids as follows: Group I, a saturated fat (coconut oil); Group II, a monounsaturated fat (olive oil); Group III, a polyunsaturated fat rich in omega-6 fatty acids (safflower oil); Group IV, same as Group III plus vitamin E; and Group V, a polyunsaturated fat rich in omega-3 fatty acids (menhaden oil). All diets contained 2% safflower oil to provide sufficient amounts of linoleic acid (an essential fatty acid). Rats were killed after six weeks of feeding the various diets, and the concentrations of beta-carotene and vitamin A were determined in plasma and liver. Plasma vitamin A levels were not altered by any of the dietary lipids or by an excess of vitamin E. The concentrations of beta-carotene in plasma were the lowest in rats fed the diet containing menhaden oil. The feeding of the diet containing an excess of vitamin E also resulted in a significant decrease in plasma beta-carotene concentration. Similarly, the hepatic beta-carotene concentration was also reduced to about one-half in rats fed the diet containing an excess of vitamin E. Liver beta-carotene concentration was higher in Groups II and III than in the other three dietary groups. Hepatic vitamin A concentrations were also affected by the type of dietary fat.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dietary lipids on hepatic and plasma beta-carotene and vitamin A levels in rats fed beta-carotene

Diets low in carotenoids have been associated with greater risks of developing certain cancers. Diets high in fats, especially unsaturated fats, have also been associated with increased risks of developing cancer. This study was undertaken to evaluate the effect of fat type on the beta-carotene status in a rat model. Rats were fed diets containing 2 g/kg beta-carotene or placebo and either 10% lard or corn oil for 13-16 weeks. Plasma vitamin A was unaffected by the dietary regimes. Liver vitamin A levels were significantly increased in the beta-carotene groups and were greater in the lard-fed animals. No detectable level of plasma beta-carotene was found in the rats fed placebo diets. In animals given dietary beta-carotene, plasma beta-carotene levels were significantly reduced in the group fed corn oil compared to the group fed lard. Liver beta-carotene levels were higher in the groups fed corn oil. The results suggest that the type of dietary fat can significantly affect the circulating and tissue levels of beta-carotene.     

Golden Rice: introducing the beta-carotene biosynthesis pathway into rice endosperm by genetic engineering to defeat vitamin A deficiency

To obtain a functioning provitamin A (beta-carotene) biosynthetic pathway in rice endosperm, we introduced in a single, combined transformation effort the cDNA coding for phytoene synthase (psy) and lycopene beta-cyclase (beta-lcy) both from Narcissus pseudonarcissus and both under the control of the endosperm-specific glutelin promoter together with a bacterial phytoene desaturase (crtI, from Erwinia uredovora under constitutive 35S promoter control). This combination covers the requirements for beta-carotene synthesis and, as hoped, yellow beta-carotene-bearing rice endosperm was obtained in the T(0)-generation. Additional experiments revealed that the presence of beta-lcy was not necessary, because psy and crtI alone were able to drive beta-carotene synthesis as well as the formation of further downstream xanthophylls. Plausible explanations for this finding are that these downstream enzymes are constitutively expressed in rice endosperm or are induced by the transformation, e.g., by enzymatically formed products. Results using N. pseudonarcissus as a model system led to the development of a hypothesis, our present working model, that trans-lycopene or a trans-lycopene derivative acts as an inductor in a kind of feedback mechanism stimulating endogenous carotenogenic genes. Various institutional arrangements for disseminating Golden Rice to research institutes in developing countries also are discussed.     

The effects of vitamin A, beta-carotene and canthaxanthin on vitamin A metabolism and immune responses in the chick

Chicks were fed diets containing, 0, 0.85 and 350 mg/kg vitamin A and 1 g/kg beta-carotene or canthaxanthin from hatching. Carotene increased and canthaxanthin depressed plasma and hepatic vitamin A concentrations. High vitamin A levels decreased the concentration of both carotenoids. Neither carotene nor canthaxanthin affected intestinal carotene cleavage in vitro. T-lymphocyte proliferative responses were decreased at low vitamin A intakes and enhanced at the high vitamin A intake. Carotene and canthaxanthin fed with 0.85 mg/kg vitamin A had no effect on immune response and with 350 mg/kg vitamin A prevented the enhancement of the proliferative response. It is concluded that immune response in the chick is modulated by vitamin A; carotene and canthaxanthin effects are probably due to influences on vitamin A metabolism.     

Zinc plus beta-carotene supplementation of pregnant women is superior to beta-carotene supplementation alone in improving vitamin A status in both mothers and infants

BACKGROUND: Deficiencies of vitamin A, iron, and zinc are prevalent in women and infants in developing countries. Supplementation during pregnancy can benefit mother and infant. OBJECTIVE: We examined whether supplementation during pregnancy with iron and folic acid plus beta-carotene or zinc or both improves the micronutrient status of mothers and infants postpartum. DESIGN: Pregnant women (n = 170) were supplemented daily only during pregnancy with beta-carotene (4.5 mg), zinc (30 mg), or both or placebo plus iron (30 mg) and folic acid (0.4 mg) in a randomized, double-blind, placebo-controlled trial. Micronutrient status was assessed 1 and 6 mo postpartum. RESULTS: Six months postpartum, plasma retinol concentrations were higher in the women who received zinc during pregnancy than in women who did not. Infants born to mothers supplemented with beta-carotene + zinc had higher plasma retinol concentrations, with the frequency of vitamin A deficiency reduced by >30% compared with the other 3 groups. Breast-milk beta-carotene concentrations were higher in all women supplemented with beta-carotene, but breast-milk retinol concentrations were higher only in women who received beta-carotene + zinc. Zinc concentrations did not differ among groups in mothers and infants. CONCLUSIONS: Zinc supplementation during pregnancy improved the vitamin A status of mothers and infants postpartum, which indicates a specific role of zinc in vitamin A metabolism. Addition of both beta-carotene and zinc to iron supplements during pregnancy could be effective in improving the vitamin A status of mothers and infants.     

Influence of dietary fat on beta-carotene absorption and bioconversion into vitamin A

Dietary fat facilitates the utilization of carotenoids and, based on serum beta-carotene or retinol responses following ingestion of meals containing carotene and fat sources, it has been reported that the amount of fat required in a meal may be minimal (approximately 3-5 g). However, the dietary fat requirement for optimal carotene utilization in humans cannot be fully ascertained without longer-term dose-response studies that measure the changes in vitamin A body stores in response to varying levels of dietary fat. In humans, vitamin A body stores can be determined by use of stable isotope-dilution methods. Animal studies have shown that although the level of dietary fat has no effect on serum vitamin A concentrations of animals fed beta-carotene, higher liver vitamin A concentrations were found in those that ingested higher fat levels. Other factors that might influence the relationship of fat intake and beta-carotene utilization include the type of fat ingested, physicochemical properties of the carotenoid source, amount of carotene ingested, whether fat and beta-carotene sources are provided in the same meal, the presence of helminthic infections, age, and vitamin A status.     

Variability of the conversion of beta-carotene to vitamin A in women measured by using a double-tracer study design

BACKGROUND: Blood beta-carotene and vitamin A responses to oral beta-carotene are variable in humans. Some individuals are characterized as responders and others as low- or nonresponders. A better understanding of the conditions that produce the variability is important to help design public health programs that ensure vitamin A sufficiency. OBJECTIVE: Our objective was to assess variability in absorption and conversion of beta-carotene to vitamin A in vivo in humans by using a novel double-tracer ?hexadeuterated (D(6)) beta-carotene and D(6) retinyl acetate approach. DESIGN: Eleven healthy women were housed at the US Department of Agriculture Western Human Nutrition Research Center metabolic unit for 44 d, where they consumed diets adequate in vitamins and minerals except for carotenoids. After an adaptation period, the women were given 30 micromol D(6) retinyl acetate orally, followed 1 wk later with 37 micromol D(6) beta-carotene (approximately equimolar doses). Time-dependent plasma concentration curves were determined for D(6) retinol, D(6) beta-carotene, and trideuterated (D(3)) retinol (derived from D(6) beta-carotene). RESULTS: Mean (+/-SE) absorption of D(6) beta-carotene was 3.3 +/- 1.3% for all subjects. The mean conversion ratio was 0.81 +/- 0.34 mol D(3) retinol to 1 mol D(6) beta-carotene for all subjects. However, only 6 of the 11 subjects had plasma D(6) beta-carotene and D(3) retinol concentrations that we could measure. The mean absorption of D(6) beta-carotene in these 6 subjects was 6.1 +/- 0.02% and their conversion ratio was 1.47 +/- 0.49 mol D(3) retinol to 1 mol D(6) beta-carotene. The remaining 5 subjects were low responders with 相似文献   

Changes in hepatic parenchymal and nonparenchymal cell vitamin A content during vitamin A depletion in the rat

Levels of total, unesterified and esterified retinol were determined in liver, liver parenchymal cells (PC) and liver nonparenchymal cells (NPC) during vitamin A depletion in rats. Liver vitamin A levels decreased from 113 to 4 micrograms over a 97-d experimental period; plasma retinol concentrations did not change significantly during this time. Initially, greater than 90% of hepatic vitamin A was in the esterified form and most (93%) was localized in NPC. During vitamin A depletion, there were significant declines in retinyl ester content of both PC and NPC, but unesterified retinol levels were not significantly affected. Plasma retinol concentrations were significantly correlated with unesterified retinol mass in PC and NPC, but not with retinyl ester mass. Although 94% of the liver's negative vitamin A balance was due to changes in NPC retinyl ester levels, the fractional rate of retinyl ester loss from PC and NPC was almost identical. Since unesterified retinol levels in plasma, PC and NPC appeared to be conserved even when liver retinyl ester stores were virtually depleted, and since the retinol utilization rate was apparently not decreasing during this stage of vitamin A depletion, these data support the hypotheses that homeostatic mechanisms controlling the three pools of unesterified retinol are linked, and that vitamin A utilization rate is maintained as long as unesterified retinol levels in plasma, PC and NPC are normal.     

Response of the insulin-like growth factor system to vitamin A depletion and repletion in rats

Vitamin A (VA) and insulin-like growth factors (IGF) are important regulators of a wide range of physiological processes. To investigate the IGF system's involvement in the physiological actions of VA, we examined the effects of VA status on components of the IGF system in rats. Male rats (3-wk-old) fed a VA-deficient diet for 11 wk developed VA deficiency, as confirmed by the depletion of serum retinol and hepatic retinyl palmitate. Rats fed the VA-deficient diet had significantly lower body weight (p < 0.05) and lower serum IGF-I concentrations than the rats fed the control diet. The decreases in serum IGF-I levels were accompanied by approximately 40% lower levels of the IGF-I mRNA in the liver and lungs. With respect to the gene expression of other IGF system components, VA deficiency caused a twofold induction of IGF-I receptor (IGF-IR) mRNA in the heart and a twofold reduction in IGFBP-6 mRNA in the lungs, but did not alter the expression of IGF-II, IGFBP-1, IGFBP-3, IGFBP-4 or IGFBP-5 in all tissues examined. When VA-deficient rats received a single injection of retinoic acid (2 mg/rat), tissue IGF-I and IGF-IR gene expression did not change after 4 or 8 h, while the expression of IGF-II, IGFBP-4, and IGFBP-6 mRNAs in some tissues increased rapidly. These results suggest a possible involvement of the IGF system in mediating the physiological actions of VA, including VA-supported growth, in the rat.     

Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity.

Isozymes of alcohol and other dehydrogenases convert ethanol and retinol to their corresponding aldehydes in vitro. In addition, new pathways of retinol metabolism have been described in hepatic microsomes that involve, in part, cytochrome P450s, which can also metabolize various drugs. In view of these overlapping metabolic pathways, it is not surprising that multiple interactions between retinol, ethanol, and other drugs occur. Accordingly, prolonged use of alcohol, drugs, or both, results not only in decreased dietary intake of retinoids and carotenoids, but also accelerates the breakdown of retinol through cross-induction of degradative enzymes. There is also competition between ethanol and retinoic acid precursors. Depletion ensues, with associated hepatic and extrahepatic pathology, including carcinogenesis and contribution to fetal defects. Correction of deficiency through vitamin A supplementation has been advocated. It is, however, complicated by the intrinsic hepatotoxicity of retinol, which is potentiated by concomitant alcohol consumption. By contrast, beta-carotene, a precursor of vitamin A, was considered innocuous until recently, when it was found to also interact with ethanol, which interferes with its conversion to retinol. Furthermore, the combination of beta-carotene with ethanol results in hepatotoxicity. Moreover, in smokers who also consume alcohol, beta-carotene supplementation promotes pulmonary cancer and, possibly, cardiovascular complications. Experimentally, beta-carotene toxicity was exacerbated when administered as part of beadlets. Thus ethanol, while promoting a deficiency of vitamin A also enhances its toxicity as well as that of beta-carotene. This narrowing of the therapeutic window for retinol and beta-carotene must be taken into account when formulating treatments aimed at correcting vitamin A deficiency, especially in drinking populations.