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Department of Pharmacology and Toxicology, University of Western
Ontario, London, Ontario, Canada N6A 5C1
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 µM
hemin, biliverdin, and bilirubin, respectively) activity. The RNA
polymerase inhibitor actinomycin D completely blocked Cyp1a1 induction
by these compounds, indicating a requirement for de novo
RNA 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.
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