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Molecular Pharmacology

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Research ArticleArticle

Dietary 9-cis-β,β-Carotene Fails to Rescue Vision in Mouse Models of Leber Congenital Amaurosis

Tadao Maeda, Lindsay Perusek, Jaume Amengual, Darwin Babino, Krzysztof Palczewski and Johannes von Lintig
Molecular Pharmacology November 2011, 80 (5) 943-952; DOI: https://doi.org/10.1124/mol.111.074732
Tadao Maeda
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Lindsay Perusek
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Jaume Amengual
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Darwin Babino
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Krzysztof Palczewski
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Johannes von Lintig
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Abstract

Synthetic 9-cis-stereoisomers of vitamin A (all-trans-retinol) are especially promising agents for the fight against blinding diseases. Several studies suggested that 9-cis-β,β-carotene (9-cis-BC), a natural and abundant β-carotene isomer in the diet, could be the precursor of 9-cis-retinoids and thus could have therapeutic applications. Here we showed that 9-cis-BC is metabolized both in vitro and in vivo by two types of mouse carotenoid oxygenases, β,β-Carotene monooxygenase 1 (BCMO1), and β,β-carotene dioxygenase 2 (BCDO2). In the symmetric oxidative cleavage reaction at C15,C15′ position by BCMO1, part of the 9-cis-double bond was isomerized to the all-trans-stereoisomer, yielding all-trans-retinal and 9-cis-retinal in a molar ratio of 3:1. The asymmetric cleaving enzyme BCDO2 preferentially removed the 9-cis-ring site at the C9,C10 double bond from this substrate, providing an all-trans-β-10′-apocarotenal product that can be further metabolized to all-trans-retinal by BCMO1. Studies in knockout mouse models confirmed that each carotenoid oxygenase can metabolize 9-cis-BC. Therefore, treatment of mouse models of Leber congenital amaurosis with 9-cis-BC and 9-cis-retinyl-acetate, a well established 9-cis-retinal precursor, showed that the cis-carotenoid was far less effective than the cis-retinoid in rescuing vision. Thus, our in vitro and in vivo studies revealed that 9-cis-BC is not a major source for mouse 9-cis-retinoid production but is mainly converted to all-trans-retinoids to support canonical vitamin A action.

Footnotes

  • K.P. and T.M. are consultants for QLT Inc.

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This research was supported in part by the National Institute of Health National Eye Institute [EY019641, EY009339, EY021126, EY019880, EY020551, P30-EY11373]; the Research to Prevent Blindness Foundation; and the Foundation Fighting Blindness. The University of Washington and QLT Inc. may commercialize some of the technology described in this work.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.074732.

  • ABBREVIATIONS:

    RPE
    retinal pigmented epithelium
    LRAT
    lecithin:retinol acyl transferase
    RPE65
    retinal pigmented epithelium protein of 65 kDa
    RP
    retinitis pigmentosa
    9-cis-BC
    9-cis-β,β-carotene
    LCA
    Leber congenital amaurosis
    BCMO1
    β,β-carotene monooxygenase 1
    BCDO2
    β,β-carotene dioxygenase 2
    9-cis-R-Ac
    9-cis-retinyl acetate
    qRT
    quantitative real-time
    PCR
    polymerase chain reaction
    EtOH
    ethanol
    MeOH
    methanol
    HPLC
    high-performance liquid chromatography
    WT
    wild-type
    DMSO
    dimethyl sulfoxide
    MOPS
    4-morpholinepropanesulfonic acid
    ERG
    electroretinogram.

  • Received July 11, 2011.
  • Accepted August 23, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (5)
Molecular Pharmacology
Vol. 80, Issue 5
1 Nov 2011
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Research ArticleArticle

9-cis-β,β-Carotene Metabolism in Mammals

Tadao Maeda, Lindsay Perusek, Jaume Amengual, Darwin Babino, Krzysztof Palczewski and Johannes von Lintig
Molecular Pharmacology November 1, 2011, 80 (5) 943-952; DOI: https://doi.org/10.1124/mol.111.074732

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Research ArticleArticle

9-cis-β,β-Carotene Metabolism in Mammals

Tadao Maeda, Lindsay Perusek, Jaume Amengual, Darwin Babino, Krzysztof Palczewski and Johannes von Lintig
Molecular Pharmacology November 1, 2011, 80 (5) 943-952; DOI: https://doi.org/10.1124/mol.111.074732
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