Transforming growth factor-beta 1 down-regulates basal and polycyclic aromatic hydrocarbon-induced cytochromes P-450 1A1 and 1A2 in adult human hepatocytes in primary culture.
The effects of interleukin (IL)-1 beta, IL-4, IL-6, tumor necrosis factor (TNF)-alpha, interferon (IFN)-alpha, IFN-gamma, and transforming growth factor (TGF)-beta 1 on cytochrome P-450 (CYP) 1A expression and polycyclic aromatic hydrocarbon (PAH)-mediated induction in primary human hepatocyte cultures were determined. Most cytokines that were previously found to decrease basal CYP expression could counteract PAH induction of CYP1A mRNA and its associated ethoxyresorufin-O-deethylation (EROD) activity. IL-1 beta and TNF-alpha blocked 3-methylcholanthrene (3-MC)-induced EROD activity by up to 25 and 44%, respectively. IFN-alpha and IFN-gamma antagonized EROD induction by up to 61 and 70%, respectively. TGF-beta 1 proved to be the most effective cytokine, because 72 hr of treatment with 2 ng/ml TGF-beta 1 produced nearly 100% inhibition of 3-MC- and benzo(a)pyrene-induced CYP1A1 and CYP1A2 mRNAs and EROD activity. Treatment with cycloheximide in combination with 3-MC led to superinduction of CYP1A mRNA, under which conditions TGF-beta 1 did not block induction, suggesting the requirement for protein synthesis for the suppressive effect of the cytokine. In addition, TGF-beta 1 augmented AP-1-binding activity, suggesting that fos and/or jun protooncogene products could be implicated in the response. Our results demonstrate that IL-1 beta, TNF-alpha, and IFNs antagonized PAH-mediated induction of CYP1A gene expression in human hepatocytes. In addition, we report the finding of a novel effect of TGF-beta 1, which was able to prevent CYP1A1 and -1A2 induction by two different PAHs.
Abdel-Razzak
Z
Z
INSERM U 49, Hôpital de Pontchaillou, Rennes, France.
Corcos
L
L
Fautrel
A
A
Campion
J P
JP
Guillouzo
A
A
D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D016207:Cytokines / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008748:Methylcholanthrene / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology*
D016207:Cytokines; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D001564:Benzo(a)pyrene; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D003513:Cycloheximide; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2