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OtherCHEMOTHERAPY/GENE THERAPY

Both the Immunosuppressant SR31747 and the Antiestrogen Tamoxifen Bind to an Emopamil-Insensitive Site of Mammalian Δ8-Δ7 Sterol Isomerase

Raymond Paul, Sandra Silve, Nathalie De Nys, Pascal-Henry Dupuy, Christine Labit-Le Bouteiller, Jorge Rosenfeld, Pascual Ferrara, Gérard Le Fur, Pierre Casellas and Gérard Loison
Journal of Pharmacology and Experimental Therapeutics June 1998, 285 (3) 1296-1302;
Raymond Paul
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Sandra Silve
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Nathalie De Nys
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Pascal-Henry Dupuy
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Christine Labit-Le Bouteiller
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Jorge Rosenfeld
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Pascual Ferrara
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Gérard Le Fur
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Pierre Casellas
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Gérard Loison
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Abstract

SR31747 is a novel agent that elicits immunosuppressive and anti-inflammatory effects. This drug was shown to inhibit Δ8-Δ7 sterol isomerase in yeast. To test whether this enzyme could also be an SR31747 target in mammals, the binding, antiproliferative and sterol biosynthesis inhibitory properties of various drugs were studied in recombinant sterol isomerase-producing yeast cells. Our results clearly show that SR31747 is a high affinity ligand of recombinant mammalian sterol isomerase (Kd = 1 nM). Tridemorph, a sterol biosynthesis inhibitor that is widely used in agriculture as an antifungal agent, is also a powerful inhibitor of murine and human sterol isomerases (IC50 value in the nanomolar range). Some drugs, like cis-flupentixol, trifluoperazine, 7-ketocholestanol and tamoxifen, inhibit SR31747 binding only with the mammalian enzymes, whereas other drugs, like haloperidol and fenpropimorph, are much more effective with the yeast enzyme than with the mammalian ones. Emopamil, a high affinity ligand of human sterol isomerase, is inefficient in inhibiting SR31747 binding to its mammalian target, suggesting that the SR31747 and emopamil binding sites on mammalian sterol isomerase do not overlap. In contrast, SR31747 binding inhibition by tamoxifen is very efficient and competitive (IC50 value in the nanomolar range), indicating that mammalian sterol isomerase contains a so-called antiestrogen binding site. Tamoxifen is found to selectively inhibit sterol biosynthesis at the sterol isomerase step in the cells that are producing the mammalian enzyme in place of their own sterol isomerase. Finally, we also show that tridemorph, a sterol biosynthesis inhibitor widely used in agriculture as an antifungal agent, is not selective of yeast Δ8-Δ7 sterol isomerase but is also highly efficient against murine Δ8-Δ7 sterol isomerase or human Δ8-Δ7 sterol isomerase. This observation contrasts with our already published results showing that fenpropimorph, another sterol isomerase inhibitor used in agriculture, is only poorly efficient against the mammalian enzymes.

Footnotes

  • Send reprint requests to: Dr. G. Loison, Sanofi-Recherche, Labège Innopole Voie I, BP 137, F-31676-Labège Cédex, France. E-mail: gerard.loison{at}tls1.elfsanofi.fr

  • ↵1 R.P. and S.S. contributed equally to this work

  • Abbreviations:
    EBP
    emopamil-binding protein
    hEBP
    human emopamil-binding protein
    SI
    Δ8-Δ7 sterol isomerase
    mSI
    murine Δ8-Δ7 sterol isomerase
    hSI
    human Δ8-Δ7 sterol isomerase
    ySI
    yeast Δ8-Δ7 sterol isomerase
    ABC
    ATPase-binding cassette
    SBI
    sterol biosynthesis inhibitor
    • Received July 15, 1997.
    • Accepted February 4, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 3
1 Jun 1998
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OtherCHEMOTHERAPY/GENE THERAPY

Both the Immunosuppressant SR31747 and the Antiestrogen Tamoxifen Bind to an Emopamil-Insensitive Site of Mammalian Δ8-Δ7 Sterol Isomerase

Raymond Paul, Sandra Silve, Nathalie De Nys, Pascal-Henry Dupuy, Christine Labit-Le Bouteiller, Jorge Rosenfeld, Pascual Ferrara, Gérard Le Fur, Pierre Casellas and Gérard Loison
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1296-1302;

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OtherCHEMOTHERAPY/GENE THERAPY

Both the Immunosuppressant SR31747 and the Antiestrogen Tamoxifen Bind to an Emopamil-Insensitive Site of Mammalian Δ8-Δ7 Sterol Isomerase

Raymond Paul, Sandra Silve, Nathalie De Nys, Pascal-Henry Dupuy, Christine Labit-Le Bouteiller, Jorge Rosenfeld, Pascual Ferrara, Gérard Le Fur, Pierre Casellas and Gérard Loison
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1296-1302;
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