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Disulfiram Metabolites Permanently Inactivate the Human Multidrug Resistance P-Glycoprotein

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Download Hi-Res ImageDownload to MS-PowerPointCite This:Mol. Pharmaceutics 2004, 1, 6, 426-433
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    Disulfiram Metabolites Permanently Inactivate the Human Multidrug Resistance P-Glycoprotein†
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    CIHR Group in Membrane Biology, Department of Medicine and Department of Biochemistry, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
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    Molecular Pharmaceutics

    Cite this: Molecular Pharmaceutics 2004, 1, 6, 426–433
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    https://doi.org/10.1021/mp049917l
    Published September 29, 2004
    Copyright © 2004 American Chemical Society
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    Abstract

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    The human multidrug resistance P-glycoprotein (P-gp) uses ATP to transport a wide variety of structurally unrelated cytotoxic compounds out of the cell. The relatively high expression of P-gp in organs such as the intestine, kidney, blood−brain/testes barrier and in some tumor cells can compromise chemotherapy treatments for patients with cancer or AIDS/HIV. It has been difficult to inhibit P-gp during chemotherapy with noncovalent inhibitors because the relatively high levels of inhibitors have severe side effects. An alternative approach to inhibit P-gp would be to covalently modify cysteine residues within the NBDs. In this study, we tested whether metabolites of disulfiram, a drug currently used to treat chronic alcoholism, could inhibit P-gp. We show that the disulfiram metabolites, S-methyl N,N-diethylthiocarbamate sulfoxide and S-methyl N,N-diethylthiocarbamate sulfone inhibited the verapamil-stimulated ATPase activity of P-gp with IC50 values (concentrations that result in 50% inhibition of activity) of 9 and 4.8 μM, respectively. Similarly, S-methyl N,N-diethylthiocarbamate sulfoxide and S-methyl N,N-diethylthiocarbamate sulfone inhibited the activity of aldehyde dehydrogenase with IC50 values of 3.2 and 1.7 μM, respectively. Inhibition of P-gp by the metabolites was not reversed by addition of the reducing compound, dithiothreitol. We then determined which endogenous cysteine residue was responsible for inhibiting P-gp activity after exposure to the disulfiram metabolites. Treatment of P-gp mutants containing a single cysteine residue showed that inactivation was primarily due to modification of Cys1074 in NBD2. These results indicate that metabolites of disulfiram can covalently inactivate P-gp. Covalent modification of drug transporters could be a useful approach for inhibiting their activities during chemotherapy.

    Keywords: P-glycoprotein; aldehyde dehydrogenase; disulfiram; disulfiram metabolites; ATPase activity; covalent inhibition

    Copyright © 2004 American Chemical Society

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    †

     This work was supported by grants from the Canadian Cancer Society through the National Cancer Institute of Canada and the Canadian Institutes for Health Research (CIHR). D.M.C. is the recipient of the Canada Research Chair in Membrane Biology.

    *

     To whom correspondence should be addressed:  Department of Medicine, University of Toronto, Room 7342, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada. Tel. or fax:  416-978-1105. E-mail:  [email protected].

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    Molecular Pharmaceutics

    Cite this: Molecular Pharmaceutics 2004, 1, 6, 426–433
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    https://doi.org/10.1021/mp049917l
    Published September 29, 2004
    Copyright © 2004 American Chemical Society
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