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Cited by 128Steroid Chemistry and BiochemistryEstrogen and related hormone effectsCholesterol and Lipid Metabolism

Identification and pharmacological characterization of cholesterol-5,6-epoxide hydrolase as a target for tamoxifen and AEBS ligands

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de Medina, Philippe, Paillasse, Michael R., Segala, Gregory, Poirot, Marc, Silvente-Poirot, Sandrine·2010·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1002922107PMC PMC2922168
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Abstract

The microsomal antiestrogen binding site (AEBS) is a high-affinity target for the antitumor drug tamoxifen and its cognate ligands that mediate breast cancer cell differentiation and apoptosis. The AEBS, a hetero-oligomeric complex composed of 3β-hydroxysterol-Δ 8 -Δ 7 -isomerase (D8D7I) and 3β-hydroxysterol-Δ 7 -reductase (DHCR7), binds different structural classes of ligands, including ring B oxysterols. These oxysterols are inhibitors of cholesterol-5,6-epoxide hydrolase (ChEH), a microsomal epoxide hydrolase that has yet to be molecularly identified. We hypothesized that the AEBS and ChEH might be related entities. We show that the substrates of ChEH, cholestan-5α,6α-epoxy-3β-ol (α-CE) and cholestan-5β,6β-epoxy-3β-ol (β-CE), and its product, cholestane-3β,5α,6β-triol (CT), are competitive ligands of tamoxifen binding to the AEBS. Conversely, we show that each AEBS ligand is an inhibitor of ChEH activity, and that there is a positive correlation between these ligands’ affinity for the AEBS and their potency to inhibit ChEH ( r 2 = 0.95; n = 39; P < 0.0001). The single expression of D8D7I or DHCR7 in COS-7 cells slightly increased ChEH activity (1.8- and 2.6-fold), whereas their coexpression fully reconstituted ChEH, suggesting that the formation of a dimer is required for ChEH activity. Similarly, the single knockdown of D8D7I or DHCR7 using siRNA partially inhibited ChEH in MCF-7 cells, whereas the knockdown of both D8D7I and DHCR7 abolished ChEH activity by 92%. Taken together, our findings strongly suggest that the AEBS carries out ChEH activity and establish that ChEH is a new target for drugs of clinical interest, polyunsaturated fatty acids and ring B oxysterols.

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  • TAM's affinity for ChEH may underlie its counter-intuitive efficacy in ER-negative breast cancers.

    “In fact, the affinity of TAM for ChEH is second only to that for ERα, which may underlie its counter-intuitive efficacy in ER-negative breast cancers [11].”

    From Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis (2015) · cites this paper as [11]

    The paper’s opening section says that, after the estrogen receptor, AEBS is tamoxifen’s highest-affinity target; the Discussion links ChEH inhibition to possible anticancer effects. But the paper does not address tamoxifen’s efficacy in ER-negative breast cancers or propose ChEH affinity as an explanation for it. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • TAM binds cholesterol epoxide hydrolase (ChEH), an enzyme complex involved in cholesterol biosynthesis.

    “Furthermore, TAM binds other endogenous molecules, including sigma 1 and 2 receptors on the endoplasmic reticulum [10], and cholesterol epoxide hydrolase (ChEH) – an enzyme complex involved in cholesterol biosynthesis [11].”

    From Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis (2015) · cites this paper as [11]

  • TAM's affinity for ChEH is second only to its affinity for ERα.

    “In fact, the affinity of TAM for ChEH is second only to that for ERα, which may underlie its counter-intuitive efficacy in ER-negative breast cancers [11].”

    From Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis (2015) · cites this paper as [11]

  • ChEH inhibition is complete even at lower (therapeutic) doses of TAM.

    “ChEH inhibition, which is complete even at lower (therapeutic) doses of TAM [11]”

    From Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis (2015) · cites this paper as [11]

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Authors
de Medina, P., Paillasse, M. R., Segala, G., Poirot, M., & Silvente-Poirot, S.
Affiliations
  • Institut National de la Santé et de la Recherche Médicale, U563, Équipe: Métabolisme, Oncogenése et Différenciation Cellulaire, 31052 Toulouse, France;
  • Université Toulouse III - Paul Sabatier (FR)
ORCID
Poirot, Marc
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2010-07-06
Volume
107
Issue
30
Pages
13520-13525
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1002922107
PMC
PMC2922168
OpenAlex
W2064188435
Cited by
128
References
44
Citations by year
2026: 9 · 2025: 1 · 2024: 3 · 2023: 12 · 2022: 3 · 2021: 12 · 2020: 9 · 2019: 5 · 2018: 11 · 2017: 7 · 2016: 10 · 2015: 7 · 2014: 7 · 2013: 11 · 2012: 16
FWCI
4.17
Type
journal article
Language
en
Update notices
correction (2010-07-30)
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • European Commission
  • Institut National de la Santé et de la Recherche Médicale
  • Centre National de la Recherche Scientifique
  • Institut National Du Cancer
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
antiestrogen binding sites, tamoxifen, DHCR7, cholestane-3β,5α,6β-triol, enzyme inhibition, protein dimerization, siRNA knockdown, breast cancer, polyunsaturated fatty acids
MeSH terms
Animals, Binding Sites, Binding, Competitive, Chlorocebus aethiops, Cholesterol, Epoxide Hydrolases, Estrogen Antagonists, Kinetics, Ligands, Microsomes, Liver, Radioligand Assay, Receptors, Estrogen, Sterols, Tamoxifen, Molecular Structure, COS Cells, Rats, Biocatalysis

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