Chemistry,distribution, and metabolism of tomato carotenoids and their impact on human health

Recent epidemiological studies have suggested that the consumption of tomatoes and tomato-based food products reduce the risk of prostate cancer in humans. This protective effect has been attributed to carotenoids, which are one of the major classes of phytochemicals in this fruit. The most abundant carotenoid in tomato is lycopene, followed by phytoene, phytofluene, zeta-carotene, gamma-carotene, beta-carotene, neurosporene, and lutein. The distribution of lycopene and related carotenoids in tomatoes and tomato-based food products has been determined by extraction and high-performance liquid chromatography-UV/Visible photodiode array detection. Detailed qualitative and quantitative analysis of human serum, milk, and organs, particularly prostate, have revealed the presence of all the aforementioned carotenoids in biologically significant concentrations. Two oxidative metabolites of lycopene, 2,6-cyclolycopene-1,5-diols A and B, which are only present in tomatoes in extremely low concentrations, have been isolated and identified in human serum, milk, organs (liver, lung, breast, liver, prostate, colon) and skin. Carotenoids may also play an important role in the prevention of age-related macular degeneration, cataracts, and other blinding disorders. Among 25 dietary carotenoids and nine metabolites routinely found in human serum, mainly (3R,3'R,6'R)-lutein, (3R,3'R)-zeaxanthin, lycopene, and their metabolites were detected in ocular tissues. In this review we identified and quantified the complete spectrum of carotenoids from pooled human retinal pigment epithelium, ciliary body, iris, lens, and in the uveal tract and in other tissues of the human eye to gain a better insight into the metabolic pathways of ocular carotenoids. Although (3R,3'R,6'R)-lutein, (3R,3'R)-zeaxanthin, and their metabolites constitute the major carotenoids in human ocular tissues, lycopene and a wide range of dietary carotenoids have been detected in high concentrations in ciliary body and retinal pigment epithelium. The possible role of lycopene and other dietary carotenoids in the prevention of age-related macular degeneration and other eye diseases is discussed.     

Mechanisms of genomic and non-genomic actions of carotenoids

Carotenoids are highly bioactive dietary compounds that have the potential to have significant effects on human health. It is becoming increasingly clear that the various biological effects that carotenoids exert could be driven via a number of different mechanisms. These include direct pro- and antioxidant effects, redox sensitive cell signalling, vitamin A signalling pathways and other as yet unidentified mechanisms. This article provides an overview of the known effects of carotenoids and discusses the use of model systems and functional genomic approaches further to elucidate their modes of action.     

Lutein, zeaxanthin, and the macular pigment

The predominant carotenoids of the macular pigment are lutein, zeaxanthin, and meso-zeaxanthin. The regular distribution pattern of these carotenoids within the human macula indicates that their deposition is actively controlled in this tissue. The chemical, structural, and optical characteristics of these carotenoids are described. Evidence for the presence of minor carotenoids in the retina is cited. Studies of the dietary intake and serum levels of the xanthophylls are discussed. Increased macular carotenoid levels result from supplementation of humans with lutein and zeaxanthin. A functional role for the macular pigment in protection against light-induced retinal damage and age-related macular degeneration is discussed. Prospects for future research in the study of macular pigment require new initiatives that will probe more accurately into the localization of these carotenoids in the retina, identify possible transport proteins and mechanisms, and prove the veracity of the photoprotection hypothesis for the macular pigments.     

The macular carotenoids: A biochemical overview

Among the more than 750 carotenoids identified in nature, only lutein, zeaxanthin, meso-zeaxanthin, and their oxidative metabolites are selectively accumulated in the macula lutea region of the human retina. These retinal carotenoids are collectively referred to as the macular pigment (MP) and are obtained only through dietary sources such as green leafy vegetables and yellow and orange fruits and vegetables. Lutein- and zeaxanthin-specific binding proteins (StARD3 and GSTP1, respectively) mediate the highly selective uptake of MP into the retina. Meso-zeaxanthin is rarely present in the diet, and its unique presence in the human eye results from metabolic conversion from dietary lutein by the RPE65 enzyme. The MP carotenoids filter high-intensity, short-wavelength visible light and are powerful antioxidants in a region vulnerable to light-induced oxidative stress. This review focuses on MP chemistry, absorption, metabolism, transport, and distribution with special emphasis on animal models used for MP study.This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.     

An update on microbial carotenoid production: application of recent metabolic engineering tools

Carotenoids are ubiquitous pigments synthesized by plants, fungi, algae, and bacteria. Industrially, carotenoids are used in pharmaceuticals, neutraceuticals, and animal feed additives, as well as colorants in cosmetics and foods. Scientific interest in dietary carotenoids has increased in recent years because of their beneficial effects on human health, such as lowering the risk of cancer and enhancement of immune system function, which are attributed to their antioxidant potential. The availability of carotenoid genes from carotenogenic microbes has made possible the synthesis of carotenoids in non-carotenogenic microbes. The increasing interest in microbial sources of carotenoid is related to consumer preferences for natural additives and the potential cost effectiveness of creating carotenoids via microbial biotechnology. In this review, we will describe the recent progress made in metabolic engineering of non-carotenogenic microorganisms with particular focus on the potential of Escherichia coli for improved carotenoid productivity. Amitabha Das and Sang-Hwal Yoon contributed equally to this work.     

The evolution of carotenoid coloration in estrildid finches: a biochemical analysis

The estrildid finches (Aves: Passeriformes: Estrildidae) of Africa, Asia, and Australia have been the focus of several recent tests of sexual selection theory. Many estrildids display bright red, orange, or yellow colors in the beak or plumage, which typically are generated by the presence of carotenoid pigments. In this study, we used high-performance liquid chromatography to investigate the carotenoid content of feathers and other colorful tissues in seven species of estrildids. Star finches (Neochmia ruficauda) and diamond firetails (Stagonopleura guttata) circulated two main dietary carotenoids (lutein and zeaxanthin) through the blood and liver and used both to acquire a yellow plumage color. However, five other estrildids (common waxbill, Estrilda astrild; black-rumped waxbill, Estrilda troglodytes; zebra waxbill, Amandava subflava; red avadavat, Amandava amandava; and zebra finch, Taeniopygia guttata) circulated these same dietary carotenoids along with two metabolites (dehydrolutein and anhydrolutein) through the blood and/or liver and used all four as yellow plumage colorants. We subsequently tracked the distribution of these pigments using a published phylogeny of estrildid finches to determine the evolutionary pattern of carotenoid metabolism in these birds. We found that finches from the most ancient tribe of estrildids (Estrildini) possessed the ability to metabolize dietary carotenoids. Although carotenoids from the most ancestral extant estrildid species have yet to be analyzed, we hypothesize (based on their relationships with other songbirds known to have such metabolic capabilities) that these finches inherited from their ancestors the capability to metabolize carotenoids. Interestingly, later in estrildid evolution, certain taxa lost the ability to metabolize dietary carotenoids (e.g., in the Poephilini), suggesting that the occurrence of carotenoid metabolism can be labile and is likely shaped by the relative costs and benefits of color signaling across different species.     

Biological actions of carotenoids

Of 600 carotenoids from natural sources that have been characterized, fewer than 10% serve as precursors of vitamin A. Many dietary carotenoids, both with and without provitamin A activity, are found in the blood and tissues of humans. beta-Carotene, the most nutritionally active carotenoid, comprises 15-30% of total serum carotenoids. Vitamin A is formed primarily by the oxygen-dependent central cleavage of beta-carotene and other provitamin A carotenoids. Several carotenoids show enhancement of the immune response, inhibition of mutagenesis, reduction of induced nuclear damage, and protection from various neoplastic events in cells, tissues, and whole animals. Carotenoids also protect against photo-induced tissue damage. Some carotenoids, including beta-carotene, quench highly reactive singlet oxygen under certain conditions and can block free radical-mediated reactions. In epidemiological studies, the intake of carotenoid-rich fruits and vegetables has been correlated with protection from some forms of cancer, particularly lung cancer. Similarly, serum beta-carotene levels have been associated with a decreased chance of developing lung cancer. It must be stressed, however, that these epidemiological associations do not show cause and effect. In this regard, long-term intervention trials with beta-carotene supplements are in progress. Whatever the results of these trials, carotenoids clearly show biological actions in animals distinct from their function as precursors of vitamin A.     

Retinal carotenoids can attenuate formation of A2E in the retinal pigment epithelium

A2E, an important constituent of lipofuscin in human retinal pigment epithelium (RPE), is thought to mediate light-induced oxidative damage associated with aging and other ocular disorders. Ocular carotenoids in overlying retinal tissues were measured by HPLC and mass spectrometry and were correlated with levels of RPE A2E. We observed a statistically significant increase in total A2E levels in human RPE/choroid with age, and A2E levels in macular regions were approximately 1/3 lower than in peripheral retinal regions of the same size. There was a statistically significant inverse correlation between peripheral retina carotenoids and peripheral RPE/choroid A2E. Prospective carotenoid supplementation studies in Japanese quail demonstrated nearly complete inhibition of A2E formation and oxidation. These findings support current recommendations to increase dietary intake of xanthophyll carotenoids in individuals at risk for macular degeneration and highlight a new potential mechanism for their protective effects—inhibition of A2E formation and oxidation in the eye.     

Parasite-mediated growth patterns and nutritional constraints in a cavity-nesting bird

1. Trade-offs between growth and immunity of nestling birds can be influenced by parasites, but the magnitude of these effects may depend on availability of critical dietary nutrients. Owing to their importance for both immune system function and growth, dietary carotenoids have the potential to mediate parasite-induced developmental strategies of avian hosts. 2. The effects of ectoparasitic blow flies Protocalliphora spp. and dietary carotenoids (lutein and zeaxanthin) on immune function and patterns of growth in nestling mountain bluebirds Sialia currucoides were investigated by combining parasite removal and carotenoid supplementation treatments in a 2 x 2 design. 3. Supplemental carotenoids enhanced nestlings' T-cell-mediated immune response following intradermal injection of phytohaemagglutinin. 4. The effect of carotenoid supplementation on rate of mass gain depended on whether broods were exposed to parasites: among parasitized broods, those receiving supplemental carotenoids gained mass more rapidly than nonsupplemented broods, whereas there was no effect of supplemental carotenoids on growth of mass in broods that had parasites removed. This suggests that additional dietary carotenoids allowed nestlings to compensate for the otherwise detrimental effects of parasites on mass gain. For length of the eighth primary feather at fledging, early and late broods differed in their response to parasitism: early broods showed an increase in feather length when parasites were removed, while nestlings in late broods had shorter feathers in the absence of parasites. We suggest that this may reflect within-season variation in parasite-mediated growth strategies of nestlings. 5. Maternal condition was positively associated with mass, condition and rate of feather growth of offspring under all conditions, and also influenced nestling immunocompetence, but only in the absence of parasites. 6. We conclude that dietary carotenoids alleviate some of the detrimental effects of parasites on nestling birds; however, parasites also appear to specifically influence other growth and resource allocation strategies, and possibly constrain maternal or genetic effects on offspring phenotype, irrespective of dietary carotenoid availability.     

Modulation of apoptotic signalling by carotenoids in cancer cells

There is a growing body of literature on the role of beta-carotene and other carotenoids in human chronic diseases, including cancer. While epidemiological evidence shows that a high dietary intake of fruits and vegetables rich in carotenoids is associated with a reduced risk for cancer, results from intervention trials indicate that supplemental beta-carotene enhances the risk of developing lung cancer incidence and mortality among smokers. A possible mechanism which can explain the dual role of carotenoids as both beneficial and harmful agents in cancer is that their excess or deficiency may bring about changes in molecular pathways involved in apoptotic signalling. Carotenoid ability in inhibiting or in enhancing apoptosis depends on several factors: carotenoid concentration, concerted action of multiple micronutrients, cell type, and redox status. This review summarizes the available evidence for a modulatory action of carotenoids on apoptosis and focuses on the main molecular pathways involved in this process.     

利用基因工程改良植物类胡萝卜素的合成

类胡萝卜素(carotenoids)是植物体内存在的一类重要天然色素物质的总称,其生物功能广泛.类胡萝卜素是人类饮食结构中重要的组成部分,并且在医药、化妆品及食品与饲料工业等方面扮演着重要的角色.类胡萝卜素还是一些维生素合成的前体,具有多种保健功能,可以提高人体免疫力,并具有抗癌的功效.目前有大量关于提高植物体内类胡萝卜素含量及定向改变其种类的研究,对类胡萝卜素代谢途径及其调控的理解是这些研究的基础.主要阐述植物天然类胡萝卜素的生物合成及利用基因工程对类胡萝卜素改良的研究进展.     

The influence of carotenoid acquisition and utilization on the maintenance of species-typical plumage pigmentation in male American goldfinches (Carduelis tristis) and northern cardinals (Cardinalis cardinalis).

Birds display a tremendous variety of carotenoid-based colors in their plumage, but the mechanisms underlying interspecific variability in carotenoid pigmentation remain poorly understood. Because vertebrates cannot synthesize carotenoids de novo, access to pigments in the diet is one proximate factor that may shape species differences in carotenoid-based plumage coloration. However, some birds metabolize ingested carotenoids and deposit pigments that differ in color from their dietary precursors, indicating that metabolic capabilities may also contribute to the diversity of plumage colors we see in nature. In this study, we investigated how the acquisition and utilization of carotenoids influence the maintenance of species-typical plumage pigmentation in male American goldfinches (Carduelis tristis) and northern cardinals (Cardinalis cardinalis). We supplemented the diet of captive goldfinches with red carotenoids to determine whether males, which are typically yellow in color, were capable of growing red plumage. We also deprived cardinals of red dietary pigments to determine whether they could manufacture red carotenoids from yellow precursors to grow species-typical red plumage. We found that American goldfinches were able to deposit novel pigments in their plumage and develop a striking orange appearance. Thus, dietary access to pigments plays a role in determining the degree to which goldfinches express carotenoid-based plumage coloration. We also found that northern cardinals grew pale red feathers in the absence of red dietary pigments, indicating that their ability to metabolize yellow carotenoids in the diet contributes to the bright red plumage that they display.     

Carotenoid actions and their relation to health and disease

Based on extensive epidemiological observation, fruits and vegetables that are a rich source of carotenoids are thought to provide health benefits by decreasing the risk of various diseases, particularly certain cancers and eye diseases. The carotenoids that have been most studied in this regard are β-carotene, lycopene, lutein and zeaxanthin. In part, the beneficial effects of carotenoids are thought to be due to their role as antioxidants. β-Carotene may have added benefits due its ability to be converted to vitamin A. Additionally, lutein and zeaxanthin may be protective in eye disease because they absorb damaging blue light that enters the eye. Food sources of these compounds include a variety of fruits and vegetables, although the primary sources of lycopene are tomato and tomato products. Additionally, egg yolk is a highly bioavailable source of lutein and zeaxanthin. These carotenoids are available in supplement form. However, intervention trials with large doses of β-carotene found an adverse effect on the incidence of lung cancer in smokers and workers exposed to asbestos. Until the efficacy and safety of taking supplements containing these nutrients can be determined, current dietary recommendations of diets high in fruits and vegetables are advised.     

Saffron and natural carotenoids: Biochemical activities and anti-tumor effects

Saffron, a spice derived from the flower of Crocus sativus, is rich in carotenoids. Two main natural carotenoids of saffron, crocin and crocetin, are responsible for its color. Preclinical studies have shown that dietary intake of some carotenoids have potent anti-tumor effects both in vitro and in vivo, suggesting their potential preventive and/or therapeutic roles in several tissues. The reports represent that the use of carotenoids without the potential for conversion to vitamin A may provide further protection and avoid toxicity. The mechanisms underlying cancer chemo-preventive activities of carotenoids include modulation of carcinogen metabolism, regulation of cell growth and cell cycle progression, inhibition of cell proliferation, anti-oxidant activity, immune modulation, enhancement of cell differentiation, stimulation of cell-to-cell gap junction communication, apoptosis and retinoid-dependent signaling. Taken together, different hypotheses for the antitumor actions of saffron and its components have been proposed such as a) the inhibitory effect on cellular DNA and RNA synthesis, but not on protein synthesis; b) the inhibitory effect on free radical chain reactions; c) the metabolic conversion of naturally occurring carotenoids to retinoids; d) the interaction of carotenoids with topoisomerase II, an enzyme involved in cellular DNA-protein interaction. Furthermore, the immunomodulatory activity of saffron was studied on driving toward Th1 and Th2 limbs of the immune system. In this mini-review, we briefly describe biochemical and immunological activities and chemo-preventive properties of saffron and natural carotenoids as an anticancer drug.     

Why Do We Expect Carotenoids to be Antioxidants in vivo?

The antioxidant properties of β-carotene, in addition to its proposed immunomodulatory effects, have often been cited as the factors underlying its role in preventing disease initiation and propagation, yet the strongest evidence for diet and cancer prevention is based on fruit and vegetable intake and not β-carotene or other dietary carotenoids, per se. In the light of the outcome of the ATBC trial, the Physicians Health Study and the premature termination of the CARET study, this review addresses the issue of the antioxidant properties of the carotenoids and poses the questions: do dietary carotenes and xanthophylls have a clear role in disease prevention and are their antioxidant properties relevant to this role? What. do we know about their mechanisms of action in vitro as free radical scavengers?     

The biosynthesis and nutritional uses of carotenoids

Carotenoids are isoprenoid molecules that are widespread in nature and are typically seen as pigments in fruits, flowers, birds and crustacea. Animals are unable to synthesise carotenoids de novo, and rely upon the diet as a source of these compounds. Over recent years there has been considerable interest in dietary carotenoids with respect to their potential in alleviating age-related diseases in humans. This attention has been mirrored by significant advances in cloning most of the carotenoid genes and in the genetic manipulation of crop plants with the intention of increasing levels in the diet. The aim of this article is to review our current understanding of carotenoid formation, to explain the perceived benefits of carotenoids in the diet and review the efforts that have been made to increase carotenoids in certain crop plants.     

Colorful songbirds metabolize carotenoids at the integument

For decades, carotenoids have attracted attention for their roles as vitamin-A precursors, antioxidants, and immunostimulants, but we still understand very little about the metabolic processes that accompany these compounds. Animals like birds use carotenoids to color their feathers and bare parts to become sexually attractive. They commonly metabolically derive their body colorants from dietary sources of carotenoids, but the sites of pigment metabolism remain unidentified. Here I test the hypothesis that songbirds manufacture their colorful feather and beak carotenoids directly at these tissues. I offer two lines of evidence to support this idea: (1) in a study of 11 colorful species from three passerine families, metabolically derived feather and beak carotenoids were found neither in the liver (a purported site of carotenoid metabolism), nor in the bloodstream (the means by which metabolites would be transported to colorful tissues from anywhere else in the body) at the time when pigments were being deposited into keratinized tissue, and (2) in a more detailed study of pigmentation in the American goldfinch Carduelis tristis , carotenoids sampled from the lipid fractions of maturing feather follicles yielded a mix of dietary and synthetic carotenoids, suggesting that this is the metabolically active site for feather-pigment production. This fresh perspective on carotenoid metabolism in animals should aid our efforts to characterize the responsible enzymes and to better understand the localized biological functions of these pigments.     

Evolutionary innovation and diversification of carotenoid‐based pigmentation in finches

The ornaments used by animals to mediate social interactions are diverse, and by reconstructing their evolutionary pathways we can gain new insights into the mechanisms underlying ornamental innovation and variability. Here, we examine variation in plumage carotenoids among the true finches (Aves: Fringillidae) using biochemical and comparative phylogenetic analyses to reconstruct the evolutionary history of carotenoid states and evaluate competing models of carotenoid evolution. Our comparative analyses reveal that the most likely ancestor of finches used dietary carotenoids as yellow plumage colorants, and that the ability to metabolically modify dietary carotenoids into more complex pigments arose secondarily once finches began to use modified carotenoids to create red plumage. Following the evolutionary “innovation” that enabled modified red carotenoid pigments to be deposited as plumage colorants, many finch species subsequently modified carotenoid biochemical pathways to create yellow plumage. However, no reversions to dietary carotenoids were observed. The finding that ornaments and their underlying mechanisms may be operating under different selection regimes—where ornamental trait colors undergo frequent reversions (e.g., between red and yellow plumage) while carotenoid metabolization mechanisms are more conserved—supports a growing empirical framework suggesting different evolutionary patterns for ornaments and the mechanistic innovations that facilitate their diversification.     

Accumulation and retention of micellar beta-carotene and lutein by Caco-2 human intestinal cells

Despite the interest in the diverse roles of dietary carotenoids in human health, little is known about the transfer of these plant pigments from foods to micelles during digestion and their subsequent transfer across the intestinal epithelium. We conducted this study to characterize the intestinal uptake of micellarized carotenoids using monolayers of differentiated Caco-2 human intestinal cells. Crystalline beta-carotene (BC) and lutein (LUT), solubilized in mixed micelles for delivery to cells, were stable in a tissue culture environment for 20 hours. Cellular accumulation of micellar BC and LUT was proportional to the media content of carotenoids at /=18 micromol/L. There was no indication that high levels of BC in medium or within cells adversely affected micellar LUT accumulation. These data support the use of the Caco-2 human cell line as a model for studying the intestinal uptake, absorption, and possible interactions of dietary carotenoids.