Carotenoid metabolites, their tissue and blood concentrations in humans and further bioactivity via retinoid receptor-mediated signalling

Abstract

Many epidemiological studies have emphasised the relation between carotenoid dietary intake and their circulating concentrations and beneficial health effect, such as lower risk of cardiometabolic diseases and cancer. However, there is dispute as to whether the attributed health benefits are due to native carotenoids or they are rather induced by their metabolites. Several categories of metabolites have been reported, most notably due to a) modifications at the cyclohexenyl-ring or the polyene chain, such as epoxides and geometric isomers, b) excentric cleavage metabolites with also alcohol-, aldehyde- or carboxylic acid-functional groups or c) centric cleaved metabolites with additional hydroxyl-, aldehyde- or carboxyl-functionalities, not counting their potential phase-II glucuronidated/sulphated derivatives. Of special interest are the apo-carotenoids, which originate in the intestine and other tissues from carotenoids cleavage by beta-carotene oxygenases 1/2 in a symmetrical/non-symmetrical fashion. These are more water soluble and more electrophilic, and therefore putative candidates for interactions with transcription factors such as NF-kB and Nrf2, as well as ligands for RAR-RXR nuclear receptor interactions. In this review, we discuss in vivo detected apo-carotenoids, their reported tissue concentrations, and potential associated health effects, focussing exclusively on the human situation and based on quantified/semi-quantified carotenoid-metabolites proven to be present in humans.

Structural Fusion of Natural and Synthetic Ligand Features Boosts RXR Agonist Potency

“…As the first RXR ligand scaffold for fusion with the natural ligand motif, we selected the indanyloxymethylphenylpropanoic acid skeleton (4; Supporting Information, Table S1), which had enabled the tuning of subtype preference by strategic methylation (5,6). 23 Though the incorporation of the acrylic acid motif into 4 was tolerated (7), and the α-methylacrylic acid conveyed slight functional RXRβ preference (8), all attempts to improve potency or subtype preference with modifications on the acrylic acid motif (9−11) or by fusion with the selectivitydriving methyl substituents of 5 and 6 (12−16) were not successful.…”

“…The nuclear retinoid X receptors (RXRα, RXRβ, RXRγ; NR2B1–3) regulate gene expression in response to ligands like 9-cis retinoic acid ( 1 , Chart ) and other fatty acids. − Due to their central role in nuclear receptor signaling as a universal heterodimer partner, RXRs are widely distributed over all tissues and linked to multiple pathologies including metabolic and inflammatory diseases, cancer, and neurodegeneration. ,,− Despite offering remarkable therapeutic potential in these various diseases, pharmacological RXR modulation is restricted by the lack of safe RXR agonists. ,, Bexarotene ( 2 ), holding approval for second-line indications in cancer treatment, is the only synthetic RXR agonist on the drug market but associated with adverse effects. − Lack of selectivity for RXR − and poor physicochemical features and pharmacokinetics , hinder the use of 2 in further therapeutic areas and also question its broad use as a reference RXR ligand . Next-generation RXR agonists with improved properties and selectivity are needed as tools to capture and exploit the unexplored therapeutic potential of RXR.…”

Deposition and enrichment of carotenoids in livestock products: An overview

“…Research has proved that the scavenger receptor class B type 1 (SR-B1) and cluster determinant 36 (CD36) are the two key membrane proteins that facilitate the absorption of carotenoids from mixed micelles. Once taken into the enterocyte, a part of the carotenoids undergoes cleavage by the enzymes β-carotene-15,15′oxygenase (BCO1) or β-carotene-9′,10′-oxygenase (BCO2), resulting in the formation of different cleavage products ( Bohn et al, 2022 ). BCO1 is responsible for catalyzing the bioconversion of provitamin A carotenoids into vitamin A, this process is detailed in the next section.…”

Human nutritional relevance and suggested nutritional guidelines for vitamin A5/X and provitamin A5/X

“…The vitamin A5/X / provitamin A5/X concept proposes novel identified physiologically- and nutritionally-occurring precursors of the recently identified lipid hormone, 9- cis -13,14-dihydroretinoic acid (9CDHRA), conclusively identified currently as the only physiologically relevant RXR-ligand (Fig. 1 B) [ 39 – 43 ].…”

“…2 Current EFSA recommendations for β-carotene (BC) with a focus on all- trans -β,β-carotene (ATBC) and our suggestions for 9- cis -β,β-carotene (9CBC). # based on our own calculations/percentile amounts based on calculations originating from Table 2 b, * relevant only when the individual is a tobacco smoker (no proposed upper limit for general population) and only a recommendations for people who are tobacco smoking in parallel to taking high-dose BC supplementation/consumption, ** relevant, when the individual is not a smoker; *** based on 10 mg/d as upper value due to EFSA suggestion [ 43 , 70 ]; **** volunteers with single treatment, Stahl et al [ 136 ] (Table 3 ) …”