Interferon-mediated changes in the expression of CYP1A1 in human B lymphoblastoid (AHH-1 TK +/-) cells.
The expression of constitutive and inducible cytochrome P450s has been shown to be downregulated by interferon through an unknown pretranslational mechanism that depresses the mRNA encoding P450 apoproteins. To establish an association between gene transcription and P450 apoprotein downregulation by interferon, we studied the effect of recombinant interferon (IFN-alpha 2a) on CYP1A1 in human B lymphoblastoid cell lines. The cHoI cell line expresses inducible native CYP1A1, while the genetically engineered derivative h1A1 v2 expresses a noninducible extrachromosomal vector-derived human CYP1A1 cDNA lacking the CYP1A1 promoter region. We characterized CYP1A1 activity, apoprotein, and mRNA by ethoxyresorufin O-deethylase activity, Western immunoblotting, and Northern blot analysis, respectively. In cHoI cells, following induction with dibenz[a,h]anthracene, interferon depressed CYP1A1 apoprotein and mRNA levels by 55 and 76%, respectively, with no detectable changes in enzyme activity. In h1A1 v2, however, interferon increased CYP1A1 activity, apoprotein, and mRNA. The depression of CYP1A1 mRNA and apoprotein levels incHoI cells, in contrast with the increase observed in h1A1 v2 cells, suggests that nuclear mechanisms are essential for interferon-mediated depression of inducible P450s. From our preliminary results we propose that interferon-mediated downregulation of CYP1A1 may result from inhibition of gene transcription.
Delaporte
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Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
Cribb
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AE
Renton
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KW
D001402:B-Lymphocytes / Q000187:drug effects* / Q000201:enzymology*; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000819:agonists / Q000494:pharmacology*; D008213:Lymphocyte Activation; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D016898:Interferon-alpha; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System