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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Transcriptional and Post-Translational Regulation of CYP1A1 by Primaquine

Veronica Werlinder, Maria Backlund, Andrei Zhukov and Magnus Ingelman-Sundberg
Journal of Pharmacology and Experimental Therapeutics April 2001, 297 (1) 206-214;
Veronica Werlinder
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Maria Backlund
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Andrei Zhukov
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Magnus Ingelman-Sundberg
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Abstract

Regulation of the CYP1A1 gene has been shown to involve the aryl hydrocarbon receptor and the CYP1A1 gene expression is induced by AhR ligands. Primaquine is an antimalarial agent that does not exhibit the structural properties of a classical AhR ligand. We have evaluated the mechanisms by which this compound induces CYP1A1 expression using rat hepatoma H4IIE cells and V79 cells stably expressing CYP1A1. In H4IIE cells, primaquine caused a time- and dose-dependent increase of CYP1A1 mRNA and protein expression. The transcriptional activation of the CYP1A1 gene by primaquine was strictly XRE-dependent, as shown by transfection of different CYP1A1 pGL3 reporter constructs in H4IIE cells, and the involvement of the AhR was shown by activation of a Gal4-AhR hybrid protein by primaquine in transfected cells. Furthermore, primaquine caused transformation of the cytosolic AhR to a DNA-binding form, in vitro, suggesting that primaquine directly activates the receptor complex. In addition to its action at the transcriptional level, primaquine caused a dose-dependent inhibition of CYP1A1 degradation with an IC50 of 3.3 μM, as seen in mammalian V79 cells. This was not due to the lysosomotropic activity of the drug since other lysosomotropic agents were ineffective. Primaquine formed a type II binding spectrum with CYP1A1 and inhibited the CYP1A1-dependent ethoxyresorufin O-deethylase activity in vitro with aKi of 1.3 μM, which is close to the IC50, suggesting that the drug protects CYP1A1 from degradation by binding at the active site. It is concluded that CYP1A1 is regulated by primaquine both on the transcriptional as well as on a post-translational level.

Footnotes

  • Send reprint requests to: Dr. Magnus Ingelman-Sundberg, Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden. E-mail:Magnus.Ingelman-Sundberg{at}imm.ki.se

  • ↵1 Present address: Biacore AB, Rapsgatan 7, 754 50 Uppsala, Sweden.

  • This work was supported by grants from AstraZeneca and from the Swedish Medical Research Council.

  • Abbreviations:
    P450
    cytochrome P450 superfamily of enzymes
    CYP1A1
    cytochrome P450 1A1
    PAH
    polycyclic aromatic hydrocarbon
    AhR
    aryl hydrocarbon receptor
    arnt
    aryl hydrocarbon receptor nuclear translocator protein
    XRE
    xenobiotic response element
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    DMSO
    dimethyl sulfoxide
    PCR
    polymerase chain reaction
    nt
    nucleotide
    CMV
    cytomegalovirus
    EMSA
    electrophoretic mobility shift assay
    • Received July 6, 2000.
    • Accepted December 1, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 297 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 297, Issue 1
1 Apr 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Transcriptional and Post-Translational Regulation of CYP1A1 by Primaquine

Veronica Werlinder, Maria Backlund, Andrei Zhukov and Magnus Ingelman-Sundberg
Journal of Pharmacology and Experimental Therapeutics April 1, 2001, 297 (1) 206-214;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Transcriptional and Post-Translational Regulation of CYP1A1 by Primaquine

Veronica Werlinder, Maria Backlund, Andrei Zhukov and Magnus Ingelman-Sundberg
Journal of Pharmacology and Experimental Therapeutics April 1, 2001, 297 (1) 206-214;
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