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Research ArticleArticle

Inactivation of Cytochrome P450s 2B1, 2B4, 2B6, and 2B11 by Arylalkynes

Elizabeth S. Roberts, Nancy Eddy Hopkins, Maryam Foroozesh, William L. Alworth, James R. Halpert and Paul F. Hollenberg
Drug Metabolism and Disposition November 1997, 25 (11) 1242-1248;
Elizabeth S. Roberts
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Nancy Eddy Hopkins
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Maryam Foroozesh
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William L. Alworth
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James R. Halpert
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Paul F. Hollenberg
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Abstract

The time-dependent loss of the 7-ethoxy-4-trifluoromethylcoumarin (EFC) O-deethylase activity of rat P450 2B1, rabbit P450 2B4, or dog P450 2B11 by 1-ethynylnaphthalene (1EN), 2-ethynylnaphthalene (2EN), 2-(1-propynyl)naphthalene (2PN), 1-ethynylanthracene (1EA), 2-ethynylanthracene, 2-ethynylphenanthrene, 3-ethynylphenanthrene, 9-ethynylphenanthrene (9EPh), 9-(1-propynyl)phenanthrene (9PPh), 4-ethynylpyrene (4EP), and 4-(1-propynyl)biphenyl (4PbP) was investigated. The rate constants for inactivation by the arylalkynes in descending order of effectiveness for the top five compounds were 9EPh>9PPh>1EN, 2EN, 2PN for 2B1, 9EPh>2EN>4EP>1EN, 1EA for 2B4, and 9EPh>1EA>4EP, 9PPh>2EN for 2B11. The size and the shape of the aromatic ring system and the placement of the alkyne functional group were important for inactivation. The most effective inactivator with all the isozymes was 9EPh. This compound also inactivated the EFC activity in microsomes from human lymphoblastoid cells expressing human P450 2B6. The specificity of 9EPh for the inhibition or inactivation of different P450 activities in microsomes from rats treated with various inducing agents was determined by measuring lidocaine, testosterone,p-nitrophenol, or erythromycin metabolism. The greatest effect was observed with the 2B-specific products from lidocaine and testosterone, whereas no effect was seen with p-nitrophenol or erythromycin. When the covalent binding of [3H]2EN to microsomal protein was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography, a radiolabeled protein band that corresponds to 2B1 was observed in the lanes containing microsomes from rats treated with phenobarbital and, to a lesser extent, pyridine and isosafrole after incubation with NADPH. When these microsomes were incubated with [3H]9EPh or [3H]1EP, two NADPH-dependent bands were radiolabeled. One corresponded to 2B1/2 and the other to a protein of approximately 59 kDa, which was observed in the lanes from phenobarbital-treated male and female rats and pyridine-treated male rats. No radiolabeled bands were observed with [3H,14C]4PbP with any of the microsomes.

Footnotes

  • Send reprint requests to: Dr. Paul F. Hollenberg, Department of Pharmacology, Medical Science Research Building III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0632.

  • ↵1 Present address: Chemistry Department, Xavier University of Louisiana.

  • This research was supported by NIH Grants CA16954 (P.F.H.), CA38192 (W.L.A.), and ES03619 (J.R.H.).

  • Abbreviations used are::
    P450
    cytochrome P450 (the system of P450 nomenclature as described in Nelson et al. (1) is used)
    reductase
    NADPH-cytochrome P450 reductase
    DLPC
    L-α-phosphatidylcholine, dilauroyl
    EFC
    7-ethoxy-4-trifluoromethylcoumarin
    HFC
    7-hydroxy-4-trifluoromethylcoumarin
    1EN
    1-ethynylnaphthalene
    2EN
    2-ethynylnaphthalene
    2PN
    2-(1-propynyl) naphthalene
    1EA
    1-ethynylanthracene
    2EA
    2-ethynylanthracene
    2EPh
    2-ethynylphenanthrene
    3EPh
    3-ethynylphenanthrene
    9EPh
    9-ethynylphenanthrene, 9PPh, 9-(1-propynyl)phenanthrene
    1EP
    1-ethynylpyrene
    4EP
    4-ethynylpyrene
    4PbP
    4-(1-propynyl)biphenyl
    PB
    phenobarbital
    βNF
    β-naphthoflavone
    PYR
    pyridine
    PCN
    pregnenolone 16α-carbonitrile
    SDS-PAGE
    sodium dodecyl sulfate-polyacrylamide gel electrophoresis
    TCPOBOP
    1,4-bis[2-(3,5-dichloropyridyloxy)]benzene
    DMSO
    dimethyl sulfoxide
    BSA
    bovine serum albumin
    MEGX
    monoethylglycinexylidide
    Me-OH lidocaine
    methylhydroxylidocaine
    MALDI-MS
    matrix-assisted laser desorption ionization mass spectrometry
    THF
    tetrahydrofuran
    • Received March 20, 1997.
    • Accepted June 10, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
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1 Nov 1997
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Research ArticleArticle

Inactivation of Cytochrome P450s 2B1, 2B4, 2B6, and 2B11 by Arylalkynes

Elizabeth S. Roberts, Nancy Eddy Hopkins, Maryam Foroozesh, William L. Alworth, James R. Halpert and Paul F. Hollenberg
Drug Metabolism and Disposition November 1, 1997, 25 (11) 1242-1248;

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Research ArticleArticle

Inactivation of Cytochrome P450s 2B1, 2B4, 2B6, and 2B11 by Arylalkynes

Elizabeth S. Roberts, Nancy Eddy Hopkins, Maryam Foroozesh, William L. Alworth, James R. Halpert and Paul F. Hollenberg
Drug Metabolism and Disposition November 1, 1997, 25 (11) 1242-1248;
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