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Molecular Pharmacology

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Research ArticleArticle

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

Natalia Mast, Joseph B. Lin and Irina A. Pikuleva
Molecular Pharmacology September 2015, 88 (3) 428-436; DOI: https://doi.org/10.1124/mol.115.099598
Natalia Mast
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio
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Joseph B. Lin
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio
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Irina A. Pikuleva
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio
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Abstract

Cytochrome P450 CYP27A1 is the only enzyme in humans converting cholesterol to 27-hydroxycholesterol, an oxysterol of multiple functions, including tissue-specific modulation of estrogen and liver X receptors. Both receptors seem to mediate adverse effects of 27-hydroxycholesterol in breast cancer when the levels of this oxysterol are elevated. The present work assessed druggability of CYP27A1 as a potential antibreast cancer target. We selected 26 anticancer and noncancer medications, most approved by the Food and Drug Administration, and evaluated them first in vitro for inhibition of purified recombinant CYP27A1 and binding to the enzyme active site. Six strong CYP27A1 inhibitors/binders were identified. These were the two antibreast cancer pharmaceuticals anastrozole and fadrozole, antiprostate cancer drug bicalutamide, sedative dexmedetomidine, and two antifungals ravuconazole and posaconazole. Anastrozole was then tested in vivo on mice, which received subcutaneous drug injections for 1 week. Mouse plasma and hepatic 27-hydroxycholesterol levels were decreased 2.6- and 1.6-fold, respectively, whereas plasma and hepatic cholesterol content remained unchanged. Thus, pharmacologic CYP27A1 inhibition is possible in the whole body and individual organs, but does not negatively affect cholesterol elimination. Our results enhance the potential of CYP27A1 as an antibreast cancer target, could be of importance for the interpretation of Femara versus Anastrozole Clinical Evaluation Trial, and bring attention to posaconazole as a potential complementary anti-breast cancer medication. More medications on the US market may have unanticipated off-target inhibition of CYP27A1, and we propose strategies for their identification.

Footnotes

    • Received April 18, 2015.
    • Accepted June 16, 2015.
  • This work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM62882] (to I.A.P.), National Institutes of Health National Eye Institute [Core Grant P30-EY11373], and a Fellowship for Summer Undergraduate Research from the American Society for Pharmacology and Experimental Therapeutics (to J.B.L.). I.A.P. is a recipient of the Jules and Doris Stein Professorship from the Research to Prevent Blindness.

  • dx.doi.org/10.1124/mol.115.099598.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (3)
Molecular Pharmacology
Vol. 88, Issue 3
1 Sep 2015
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Research ArticleArticle

CYP27A1 Inhibition by Marketed Drugs

Natalia Mast, Joseph B. Lin and Irina A. Pikuleva
Molecular Pharmacology September 1, 2015, 88 (3) 428-436; DOI: https://doi.org/10.1124/mol.115.099598

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Research ArticleArticle

CYP27A1 Inhibition by Marketed Drugs

Natalia Mast, Joseph B. Lin and Irina A. Pikuleva
Molecular Pharmacology September 1, 2015, 88 (3) 428-436; DOI: https://doi.org/10.1124/mol.115.099598
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