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Research ArticleArticle

Aryl Hydrocarbon Receptor-Dependent Induction of Cyp1a1 by Bilirubin in Mouse Hepatoma Hepa 1c1c7 Cells

Christopher J. Sinal and John R. Bend
Molecular Pharmacology October 1997, 52 (4) 590-599; DOI: https://doi.org/10.1124/mol.52.4.590
Christopher J. Sinal
Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada N6A 5C1
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John R. Bend
Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada N6A 5C1
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Abstract

Heme metabolism normally involves enzymatic conversion to biliverdin and subsequently to bilirubin, catalyzed by heme oxygenase and biliverdin reductase, respectively. We examined the ability of exogenously added hemin, biliverdin, or bilirubin to regulate Cyp1a1, an enzyme that may be active in bilirubin elimination. A substantial dose-dependent increase in Cyp1a1 mRNA occurred after treatment of Hepa 1c1c7 cells with either of the three compounds. This increase was readily apparent 1 hr after treatment with biliverdin or bilirubin but required ≥2 hr with hemin. Treatment of Hepa 1c1c7 cells with these compounds also caused a dose-dependent increase in Cyp1a1-dependent 7-ethoxyresorufin-O-deethylase (EROD) activity. Of the three compounds, bilirubin produced the greatest maximal increase in Cyp1a1 mRNA and EROD (5.5-, 10.5-, and 15-fold for 100 μmhemin, biliverdin, and bilirubin, respectively) activity. The RNA polymerase inhibitor actinomycin D completely blocked Cyp1a1 induction by these compounds, indicating a requirement for de novoRNA synthesis via transcriptional activation. The protein synthesis inhibitor cycloheximide did not affect Cyp1a1 mRNA induction, indicating a lack of requirement for labile protein factors. In contrast, EROD induction by hemin, biliverdin, or bilirubin was completely blocked by cycloheximide treatment, indicating that the increase in enzyme activity is dependent on increased Cyp1a1 apoprotein synthesis. Aryl hydrocarbon receptor (AHR)- and AHR nuclear translocator-deficient mutant Hepa 1c1c7 cells did not exhibit increased Cyp1a1 mRNA or EROD activity after treatment with these compounds, indicating the requirement for a functional AHR for this response. Consistent with this, hemin, biliverdin, and bilirubin were able to induce expression of the dioxin-response element/luciferase reporter plasmid pGudLuc1.1 after transient transfection into wild-type Hepa 1c1c7 cells. Gel retardation assays demonstrated that bilirubin, but not hemin or biliverdin, was able to transform the AHR to a form capable of specifically binding to a 32P-labeled oligonucleotide containing a dioxin-response element sequence. These data indicate that bilirubin induces Cyp1a1 gene transcription through direct interaction with the AHR. In contrast, hemin and biliverdin seem to induce Cyp1a1 indirectly by serving as precursors to the endogenous formation of bilirubin via normal heme metabolism pathways. This is the first direct demonstration that the endogenous heme metabolite bilirubin can directly regulate Cyp1a1 gene expression and enzymatic activity in an AHR-dependent manner.

Footnotes

    • Received March 7, 1997.
    • Accepted June 17, 1997.
  • Send reprint requests to: Dr. John R. Bend, Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada N6A 5C1. E-mail:jbend{at}julian.uwo.ca

  • This work was supported by Medical Research Council of Canada Grant MT9972 (J.R.B.). C.J.S is the recipient of an Ontario Graduate Scholarship.

  • 1 In accordance with standard convention (1), Cyp1a1 is used throughout this report in reference to the mouse isoform only. The same isoform is referred to as CYP1A1 in all other species.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 52 (4)
Molecular Pharmacology
Vol. 52, Issue 4
1 Oct 1997
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Research ArticleArticle

Aryl Hydrocarbon Receptor-Dependent Induction of Cyp1a1 by Bilirubin in Mouse Hepatoma Hepa 1c1c7 Cells

Christopher J. Sinal and John R. Bend
Molecular Pharmacology October 1, 1997, 52 (4) 590-599; DOI: https://doi.org/10.1124/mol.52.4.590

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Research ArticleArticle

Aryl Hydrocarbon Receptor-Dependent Induction of Cyp1a1 by Bilirubin in Mouse Hepatoma Hepa 1c1c7 Cells

Christopher J. Sinal and John R. Bend
Molecular Pharmacology October 1, 1997, 52 (4) 590-599; DOI: https://doi.org/10.1124/mol.52.4.590
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