COMMON PATHWAYS OF CYTOCHROME-P450 GENE-REGULATION BY PEROXISOME PROLIFERATORS AND BARBITURATES IN BACILLUS-MEGATERIUM ATCC14581

Bacillus megaterium contains a barbiturate-inducible cytochrome P450(B M-3), which catalyzes the hydroxylation of fatty acids. We report the intriguing finding that peroxisome proliferators, a major class of epi genetic carcinogen, are also extremely potent inducers of this enzyme being up to 50-fold more potent than one of the most effective barbitu rates, secobarbital. Similar to barbiturates, the mechanism of inducti on appears to involve the direct binding of the peroxisome proliferato r to the transcriptional repressor (Bm3R1), resulting in its dissociat ion from its DNA operator. These observations provide evidence that pe roxisome proliferators can interact with a transcription factor to mod ulate gene expression. The data also demonstrate that the effects of t hese compounds are highly conserved through evolution and that there a re important common denominators in the regulation of gene expression by peroxisome proliferators and the barbiturates. Evidence is presente d to indicate that this may involve effects on unsaturated fatty acid homeostasis.