Induction of cytochrome P-450 BM-3 (CYP 102) by non-steroidal anti-inflammatory drugs in Bacillus megaterium.
Bacillus megaterium contains a cytochrome P-450 fatty acid mono-oxygenase which is inducible with barbiturate drugs. We have demonstrated that this enzyme system is inducible with peroxisome proliferators. In mammals, peroxisome proliferators also induce mono-oxygenases in the CYP4A gene family. In this paper we demonstrate that the non-steroidal anti-inflammatory drugs ibuprofen, ketoprofen and indomethacin are potent inducers of fatty acid mono-oxygenase activity as well as of P-450BM-3 protein in B. megaterium. The levels of induction of P-450 protein were 11.8-, 3.9- and 3.0-fold respectively. In addition, we demonstrate that these inducing agents interact with a transcriptional repressor, Bm3R1, which leads to its dissociation from its operator sequence. This provides a rational mechanism for the induction process. This is the first report which demonstrates that non-steroidal anti-inflammatory drugs can interact directly with a transcription factor to initiate gene expression, and further substantiates the structure-activity relationships that identify inducers of cytochrome P-450BM-3 and compounds that have the potential to act as peroxisome proliferators and induce CYP4A expression in mammals.
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Imperial Cancer Research Fund, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, U.K.
Hughes
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Wolf
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D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001410:Bacillus megaterium / Q000187:drug effects / Q000201:enzymology*; D001426:Bacterial Proteins / Q000378:metabolism; D001483:Base Sequence; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D004790:Enzyme Induction; D015870:Gene Expression / Q000187:drug effects*; D007052:Ibuprofen / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007660:Ketoprofen / Q000494:pharmacology; D007700:Kinetics; D008322:Mammals; D006899:Mixed Function Oxygenases / Q000096:biosynthesis* / Q000378:metabolism; D008969:Molecular Sequence Data; D009251:NADPH-Ferrihemoprotein Reductase; D009838:Oligodeoxyribonucleotides; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001426:Bacterial Proteins; D009838:Oligodeoxyribonucleotides; D012097:Repressor Proteins; D014157:Transcription Factors; C073493:Bm3R1 protein, Bacillus megaterium; D003577:Cytochrome P-450 Enzyme System; D007660:Ketoprofen; D006899:Mixed Function Oxygenases; D009251:NADPH-Ferrihemoprotein Reductase; C052423:flavocytochrome P450 BM3 monoxygenases; D007052:Ibuprofen; D007213:Indomethacin