(01-07-15) Naturally Occurring Eccentric Cleavage Products of Provitamin A β-Carotene Function as Antagonists of Retinoic Acid Receptors*

Abdulkerim Eroglu,‡§ Damian P. Hruszkewycz,¶ Carlo dela Sena,‡§ Sureshbabu Narayanasamy,‡¶ Ken M. Riedl,‖ Rachel E. Kopec,‖ Steven J. Schwartz,‖ Robert W. Curley, Jr.,§¶ and Earl H. Harrison‡§,1
From the ‡Department of Human Nutrition,
§Ohio State Biochemistry Program,
¶College of Pharmacy, and
‖Department of Food Science & Technology, The Ohio State University, Columbus, Ohio 43210
1 To whom correspondence should be addressed: 350 Campbell Hall, 1787 Neil Ave., Columbus, OH 43210., Tel.: Phone: 614-292-8189; Fax: 614-292-8880; E-mail: [email protected].
Author information ► Article notes ► Copyright and License information ►
Received 2011 Nov 17; Revised 2012 Mar 8
Copyright © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
This article has been cited by other articles in PMC.
Go to:
Abstract
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). Eccentric cleavage of β-carotene at non-central double bonds is catalyzed by other enzymes and can also occur non-enzymatically. The products of these reactions are β-apocarotenals and β-apocarotenones, whose biological functions in mammals are unknown. We used reporter gene assays to show that none of the β-apocarotenoids significantly activated RARs. Importantly, however, β-apo-14′-carotenal, β-apo-14′-carotenoic acid, and β-apo-13-carotenone antagonized ATRA-induced transactivation of RARs. Competitive radioligand binding assays demonstrated that these putative RAR antagonists compete directly with retinoic acid for high affinity binding to purified receptors. Molecular modeling studies confirmed that β-apo-13-carotenone can interact directly with the ligand binding site of the retinoid receptors. β-Apo-13-carotenone and the β-apo-14′-carotenoids inhibited ATRA-induced expression of retinoid responsive genes in Hep G2 cells. Finally, we developed an LC/MS method and found 3–5 nm β-apo-13-carotenone was present in human plasma. These findings suggest that β-apocarotenoids function as naturally occurring retinoid antagonists. The antagonism of retinoid signaling by these metabolites may have implications for the activities of dietary β-carotene as a provitamin A and as a modulator of risk for cardiovascular disease and cancer.

Conclusions and Implications
Our results demonstrate that β-carotene can generate both RAR agonists (ATRA) and RAR antagonists (β-apo-14′-carotenal and β-apo-13-carotenone) depending on the extent of cleavage at the central C15–C15′ double bond or the C13–14 double bond, respectively. These findings may have implications for the unexpected and negative effects of high doses of β-carotene in human clinical trials of cancer prevention (25). An example is the now famous CARET trial, which, based on observational epidemiology, explored whether supplemental β-carotene would decrease incidence of lung cancer in a highly susceptible population, namely smokers and asbestos workers (26, 27). Surprisingly, the supplemented subjects had a higher incidence of disease, and the trial had to be halted early. It was apparent that the doses of β-carotene used in the trial (30 mg/day) were much higher than the range of normal dietary intakes associated with a decreased risk of disease in the observational studies (25). The possible mechanisms involved were explored in elegant studies employing a novel animal model, the smoking ferret (24, 28). These studies revealed that under conditions of high dietary β-carotene and the oxidative stress of smoking, there was a clear increase in preneoplastic lung cancer lesions in the animals. The authors concluded that oxidative stress led to increased eccentric cleavage of β-carotene and that the mixture of cleavage products led to disruption of retinoid signaling via indirect mechanisms. The present work demonstrates that specific β-apocarotenoids exert an anti-vitamin A activity by directly interacting with RARs as high affinity antagonists. Our analyses of both β-carotene-containing animal diets and fruits containing β-carotene suggest that any dietary source of β-carotene also contains β-apocarotenoids. It may also be useful to consider these findings in attempts to alleviate vitamin A deficiency in humans through the biofortification of crops with high levels of β-carotene.

SOURCE:
J Biol Chem. 2012 May 4; 287(19): 15886–15895.
Published online 2012 Mar 14. doi:  10.1074/jbc.M111.325142
PMCID: PMC3346154

News

---

In evidenza

"L'informazione presente nel sito serve a migliorare, e non a sostituire, il rapporto medico-paziente."

Per coloro che hanno problemi di salute si consiglia di consultare sempre il proprio medico curante.