Uptake and metabolism of β-apo-8'-carotenal, β-apo-10'-carotenal, and β-apo-13-carotenone in Caco-2 cells.

β-Apocarotenoids are eccentric cleavage products of carotenoids formed by chemical and enzymatic oxidations. They occur in foods containing carotenoids and thus might be directly absorbed from the diet. However, there is limited information about their intestinal absorption.

Limited appearance of apocarotenoids is observed in plasma after consumption of tomato juices: a randomized human clinical trial.

Background: Nonvitamin A apocarotenoids occur in foods. Some function as retinoic acid receptor antagonists in vitro, though it is unclear if apocarotenoids are absorbed or accumulate to levels needed to elicit biological function.

Objective: The aim of this study was to quantify carotenoids and apocarotenoids (β-apo-8'-, -10'-, -12'-, and -14'-carotenal, apo-6'-, -8'-, -10'-, -12'-, and -14'-lycopenal, retinal, acycloretinal, β-apo-13-carotenone, and apo-13-lycopenone) in human plasma after controlled consumption of carotenoid-rich tomato juices.

4-HPR Is an Endoplasmic Reticulum Stress Aggravator and Sensitizes Breast Cancer Cells Resistant to TRAIL/Apo2L.

Background/aim: N-(4-hydroxyphenyl)retinamide (4-HPR) is a synthetic retinoid, less toxic than the parent all-trans retinoic acid (RA). Unlike RA, 4-HPR induces apoptosis in tumor cells. Because 4-HPR can hydrolyze to liberate RA, a potent human teratogen, the unhydrolyzable ketone analog of 4-HPR, 4-hydroxybenzylretinone (4-HBR) has been prepared and has been found to cause apoptosis in tumor cells and shrink carcinogen-induced rat mammary tumors as 4-HPR does.

β-apo-10'-carotenoids support normal embryonic development during vitamin A deficiency.

Vitamin A deficiency is still a public health concern affecting millions of pregnant women and children. Retinoic acid, the active form of vitamin A, is critical for proper mammalian embryonic development. Embryos can generate retinoic acid from maternal circulating β-carotene upon oxidation of retinaldehyde produced via the symmetric cleavage enzyme β-carotene 15,15'-oxygenase (BCO1).

Differential Effect of Wortmannolone Derivatives on MDA-MB-231 Breast Cancer Cells.

Background/aim: The survival rate of women diagnosed with triple-negative breast-cancer (TNBC) remains low. Hence, this study aimed at the chemical and biological optimization of furanosteroid derivatives for the treatment of this type of malignancy using TNBC cells.

Materials And Methods: Semi-synthetic analogs of wortmannolone () that negatively affected the aberrant pathways in tumor cells were evaluated in hormone-independent breast cancer cells using western blot and cell-cycle analysis.

Synthesis of apo-13- and apo-15-lycopenoids, cleavage products of lycopene that are retinoic acid antagonists.

Consumption of the tomato carotenoid, lycopene, has been associated with favorable health benefits. Some of lycopene's biological activity may be due to metabolites resulting from cleavage of the lycopene molecule. Because of their structural similarity to the retinoic acid receptor (RAR) antagonist, β-apo-13-carotenone, the "first half" putative oxidative cleavage products of the symmetrical lycopene have been synthesized.

Carotenoids and Retinoids: Nomenclature, Chemistry, and Analysis.

Carotenoids are polyenes synthesized in plants and certain microorganisms and are pigments used by plants and animals in various physiological processes. Some of the over 600 known carotenoids are capable of metabolic conversion to the essential nutrient vitamin A (retinol) in higher animals. Vitamin A also gives rise to a number of other metabolites which, along with their analogs, are known as retinoids.

An HPLC-MS/MS method for the separation of α-retinyl esters from retinyl esters.

Enzymatic cleavage of the nonsymmetric provitamin A carotenoid α-carotene results in one molecule of retinal (vitamin A), and one molecule of α-retinal, a biologically inactive analog of true vitamin A. Due to structural similarities, α-retinyl esters and vitamin A esters typically coelute, resulting in the overestimation of vitamin A originating from α-carotene. Herein, we present a set of tools to identify and separate α-retinol products from vitamin A.

β-Apo-10'-carotenoids Modulate Placental Microsomal Triglyceride Transfer Protein Expression and Function to Optimize Transport of Intact β-Carotene to the Embryo.

β-Carotene is an important source of vitamin A for the mammalian embryo, which depends on its adequate supply to achieve proper organogenesis. In mammalian tissues, β-carotene 15,15'-oxygenase (BCO1) converts β-carotene to retinaldehyde, which is then oxidized to retinoic acid, the biologically active form of vitamin A that acts as a transcription factor ligand to regulate gene expression. β-Carotene can also be cleaved by β-carotene 9',10'-oxygenase (BCO2) to form β-apo-10'-carotenal, a precursor of retinoic acid and a transcriptional regulator per se The mammalian embryo obtains β-carotene from the maternal circulation.

Complementary shifts in photoreceptor spectral tuning unlock the full adaptive potential of ultraviolet vision in birds.

Color vision in birds is mediated by four types of cone photoreceptors whose maximal sensitivities (λmax) are evenly spaced across the light spectrum. In the course of avian evolution, the λmax of the most shortwave-sensitive cone, SWS1, has switched between violet (λmax > 400 nm) and ultraviolet (λmax < 380 nm) multiple times. This shift of the SWS1 opsin is accompanied by a corresponding short-wavelength shift in the spectrally adjacent SWS2 cone.

Substrate Specificity of Purified Recombinant Chicken β-Carotene 9',10'-Oxygenase (BCO2).

Provitamin A carotenoids are oxidatively cleaved by β-carotene 15,15'-dioxygenase (BCO1) at the central 15-15' double bond to form retinal (vitamin A aldehyde). Another carotenoid oxygenase, β-carotene 9',10'-oxygenase (BCO2) catalyzes the oxidative cleavage of carotenoids at the 9'-10' bond to yield an ionone and an apo-10'-carotenoid. Previously published substrate specificity studies of BCO2 were conducted using crude lysates from bacteria or insect cells expressing recombinant BCO2.

Improved Synthesis of the -Glucuronide/Glycoside of 4-Hydroxybenzylretinone (4-HBR).

Improvements in the synthesis of carbon-linked glucuronide/glucoside conjugates of cancer chemopreventive retinoids have been achieved starting with 2,3,4,6-tetra--benzyl-D-glucopyranose. The revised approach demonstrates better yields, eliminates the use of an expensive, carcinogenic protecting group reagent, and avoids much painstaking chromatography. The new approach should allow synthesis of larger quantities of the agents for detailed animal and mechanistic studies.

Actions of β-apo-carotenoids in differentiating cells: differential effects in P19 cells and 3T3-L1 adipocytes.

β-Apo-carotenoids, including β-apo-13-carotenone and β-apo-14'-carotenal, are potent retinoic acid receptor (RAR) antagonists in transactivation assays. We asked how these influence RAR-dependent processes in living cells. Initially, we explored the effects of β-apo-13-carotenone and β-apo-14'-carotenal on P19 cells, a mouse embryonal carcinoma cell line that differentiates into neurons when treated with all-trans-retinoic acid.

β-Apo-13-carotenone regulates retinoid X receptor transcriptional activity through tetramerization of the receptor.

Retinoid X receptor (RXRα) is activated by 9-cis-retinoic acid (9cRA) and regulates transcription as a homodimer or as a heterodimer with other nuclear receptors. We have previously demonstrated that β-apo-13-carotenone, an eccentric cleavage product of β-carotene, antagonizes the activation of RXRα by 9cRA in mammalian cells overexpressing this receptor. However, the molecular mechanism of β-apo-13-carotenone's modulation on the transcriptional activity of RXRα is not understood and is the subject of this report.

Cardiac dysfunction in β-carotene-15,15'-dioxygenase-deficient mice is associated with altered retinoid and lipid metabolism.

Dietary carotenoids like β-carotene are converted within the body either to retinoid, via β-carotene-15,15'-dioxygenase (BCO1), or to β-apo-carotenoids, via β-carotene-9',10'-oxygenase 2. Some β-apo-carotenoids are potent antagonists of retinoic acid receptor (RAR)-mediated transcriptional regulation, which is required to ensure normal heart development and functions. We established liquid chromatography tandem mass spectrometery methods for measuring concentrations of 10 β-apo-carotenoids in mouse plasma, liver, and heart and assessed how these are influenced by Bco1 deficiency and β-carotene intake.

The human enzyme that converts dietary provitamin A carotenoids to vitamin A is a dioxygenase.

β-Carotene 15-15'-oxygenase (BCO1) catalyzes the oxidative cleavage of dietary provitamin A carotenoids to retinal (vitamin A aldehyde). Aldehydes readily exchange their carbonyl oxygen with water, making oxygen labeling experiments challenging. BCO1 has been thought to be a monooxygenase, incorporating oxygen from O2 and H2O into its cleavage products.

Chirally deuterated benzyl chlorides from benzyl alcohols via hexachloroacetone/polymer-supported triphenylphosphine: synthesis of protected (2S, 3S)-[3-(2)H, (15)N]-tyrosine.

Chirally deuterated benzyl chlorides were prepared using novel, general hexachloroacetone/polymer-supported triphenylphosphine treatment of chirally deuterated benzyl alcohols. Doubly labeled protected tyrosine was obtained in 62% yield with 86% de at the α-carbon and 82% de at the β-carbon. Key in the synthesis was the alkylation of (15)N-labeled (-)-8-phenylmenthylhippurate with R-(-)-4-triisopropylsilyloxybenzyl-α-d chloride.

Substrate specificity of purified recombinant human β-carotene 15,15'-oxygenase (BCO1).

Humans cannot synthesize vitamin A and thus must obtain it from their diet. β-Carotene 15,15'-oxygenase (BCO1) catalyzes the oxidative cleavage of provitamin A carotenoids at the central 15-15' double bond to yield retinal (vitamin A). In this work, we quantitatively describe the substrate specificity of purified recombinant human BCO1 in terms of catalytic efficiency values (kcat/Km).

Naturally occurring eccentric cleavage products of provitamin A β-carotene function as antagonists of retinoic acid receptors.

β-Carotene is the major dietary source of provitamin A. Central cleavage of β-carotene catalyzed by β-carotene oxygenase 1 yields two molecules of retinaldehyde. Subsequent oxidation produces all-trans-retinoic acid (ATRA), which functions as a ligand for a family of nuclear transcription factors, the retinoic acid receptors (RARs).

4-Hydroxybenzyl modification of the highly teratogenic retinoid, 4-[(1E)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-propen-1-yl]benzoic acid (TTNPB), yields a compound that induces apoptosis in breast cancer cells and shows reduced teratogenicity.

Retinoids are a class of compounds with structural similarity to vitamin A. These compounds inhibit the proliferation of many cancer cell lines but have had limited medical application as they are often toxic at therapeutic levels. Efforts to synthesize retinoids with a greater therapeutic index have met with limited success.

Efficient, Low-Cost Synthesis of Retinal (Vitamin A Aldehyde).

Inexpensive retinyl acetate has been subjected to transesterification followed by allylic oxidation to give retinal in 98% yield as a 92:8 mixture of all-trans/13-cis isomers after chromatographic separation. More convenient methods of isolating the all-trans isomer have also been employed.

Retinoid chemistry: synthesis and application for metabolic disease.

In this review a discussion of the usual procedures used to synthesize retinoids is followed by an overview of the structure-activity relationships of these molecules. The discussion is then focused on the role and impact of retinoids on metabolic disorders with a particular emphasis on obesity, diabetes, and the metabolic syndrome. In these areas, both natural and synthetic retinoids that are being studied are reviewed and areas where likely future research will occur are suggested.

Identification of dihydroceramide desaturase as a direct in vitro target for fenretinide.

The dihydroceramide desaturase (DES) enzyme is responsible for inserting the 4,5-trans-double bond to the sphingolipid backbone of dihydroceramide. We previously demonstrated that fenretinide (4-HPR) inhibited DES activity in SMS-KCNR neuroblastoma cells. In this study, we investigated whether 4-HPR acted directly on the enzyme in vitro.

Carotene and novel apocarotenoid concentrations in orange-fleshed Cucumis melo melons: determinations of β-carotene bioaccessibility and bioavailability.

Muskmelons, both cantaloupe (Cucumis melo Reticulatus Group) and orange-fleshed honeydew (C. melo Inodorus Group), a cross between orange-fleshed cantaloupe and green-fleshed honeydew, are excellent sources of β-carotene. Although β-carotene from melon is an important dietary antioxidant and precursor of vitamin A, its bioaccessibility/bioavailability is unknown.

Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure.

Background And Purpose: High plasma levels of fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] were associated with improved outcome in a phase II clinical trial. Low bioavailability of 4-HPR has been limiting its therapeutic applications. This study characterized metabolism of 4-HPR in humans and mice, and to explore the effects of ketoconazole, an inhibitor of CYP3A4, as a modulator to increase 4-HPR plasma levels in mice and to increase the low bioavailability of 4-HPR.