Common pathways of cytochrome P450 gene regulation by peroxisome proliferators and barbiturates in Bacillus megaterium ATCC14581.
Bacillus megaterium contains a barbiturate-inducible cytochrome P450BM-3, which catalyzes the hydroxylation of fatty acids. We report the intriguing finding that peroxisome proliferators, a major class of epigenetic carcinogen, are also extremely potent inducers of this enzyme being up to 50-fold more potent than one of the most effective barbiturates, secobarbital. Similar to barbiturates, the mechanism of induction appears to involve the direct binding of the peroxisome proliferator to the transcriptional repressor (Bm3R1), resulting in its dissociation from its DNA operator. These observations provide evidence that peroxisome proliferators can interact with a transcription factor to modulate gene expression. The data also demonstrate that the effects of these compounds are highly conserved through evolution and that there are important common denominators in the regulation of gene expression by peroxisome proliferators and the barbiturates. Evidence is presented to indicate that this may involve effects on unsaturated fatty acid homeostasis.
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Molecular Pharmacology Unit, Ninewells Hospital and Medical School, Dundee, United Kingdom.
Hughes
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Wolf
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D001410:Bacillus megaterium / Q000201:enzymology / Q000235:genetics*; D001426:Bacterial Proteins / Q000378:metabolism; D001463:Barbiturates / Q000494:pharmacology*; D001483:Base Sequence; D002273:Carcinogens / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004269:DNA, Bacterial / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005227:Fatty Acids / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D006900:Hydroxylation; D008830:Microbodies; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000235:genetics*; D008969:Molecular Sequence Data; D009251:NADPH-Ferrihemoprotein Reductase; D009875:Operator Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D001426:Bacterial Proteins; D001463:Barbiturates; D002273:Carcinogens; D004269:DNA, Bacterial; D005227:Fatty Acids; D012097:Repressor Proteins; D014157:Transcription Factors; C073493:Bm3R1 protein, Bacillus megaterium; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D009251:NADPH-Ferrihemoprotein Reductase; C052423:flavocytochrome P450 BM3 monoxygenases