Common pathways of cytochrome P450 gene regulation by peroxisome proliferators and barbiturates in Bacillus megaterium ATCC14581.

Abstract

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.