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The Mechanism of Fenretinide (4-HPR) Inhibition of β-carotene Monooxygenase 1. New Suspect for the Visual Side Effects of Fenretinide

  • Eugenia Poliakov
  • Alexander Gubin
  • James Laird
  • Susan Gentleman
  • Robert G. Salomon
  • T. Michael RedmondEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)

Abstract

Fenretinide (4-hydroxy(phenyl)retinamide; 4-HPR), a synthetic retinoid derivative, shows anticancer potential in clinical trials for treatment of breast cancer. Common side effects associated with fenretinide treatment include night blindness initially attributed to inhibition of RBP4 (retinol-binding protein 4)-binding to retinol and consequent impaired retinol transport. However, fenretinide affects RBP4−/− animals similarly to wild-type mice, and thus, the reason for the effects of fenretinide remains elusive. It has been suggested that ®-carotene monooxygenase 1 (BCMO1) might supply all-trans retinal as an accessory source of vitamin A for the visual cycle. We found that fenretinide is a strong inhibitor of mouse BCMO1 (K i ∼ 1.2 μM), acting noncompetitively. In contrast, other retinoids, such as retinyl palmitate and retinyl acetate, as well as other biologically active aromatic compounds (capsaicin and resveratrol, and the amino analog of fenretinide) do not substantially inhibit BCMO1 activity. To study the mechanism of inhibition, we deleted portion of an interstrand loop of BCMO1 (metazoan loop) to generate BCMO1⊗336-345. This mutant had impaired enzymatic activity, but was not substantially inhibited by fenretinide. Thus, we demonstrate that fenretinide is a strong noncompetitive inhibitor of BCMO1 and that the metazoan loop influences binding of this retinoid. Our data point to an additional mechanism of fenretinide-induced night blindness through inhibition of BCMO1.

Keywords

®-carotene monooxygenase 1 BCMO1 β-carotene Fenretinide 4-HPR Noncompetitive inhibition Retinoid 

Notes

Acknowledgments

We would like to thank Dr. K. Palczewski for the enthusiastic support of this project. We would like to acknowledge Dr. W. Samuel for kindly providing fenretinide.

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Eugenia Poliakov
    • 1
  • Alexander Gubin
    • 1
  • James Laird
    • 2
  • Susan Gentleman
    • 1
  • Robert G. Salomon
    • 2
  • T. Michael Redmond
    • 1
    Email author
  1. 1.LRCMB, National Eye Institute, NIHBethesdaUSA
  2. 2.Department of ChemistryCase Western Reserve UniversityClevelandUSA

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