Antioxidant-mediated attenuation of the induction of cytochrome P450BM-3(CYP102) by ibuprofen in Bacillus megaterium ATCC 14581.
Bacillus megaterium contains a soluble cytochrome P450 termed BM-3, which is highly inducible by barbiturates, peroxisome proliferators, and nonsteroidal antiinflammatory drugs. In rats and mice, the chronic administration of peroxisome proliferators induces a sustained oxidative stress in hepatic tissue and may be responsible for the nongenotoxic carcinogenesis observed with prolonged treatment. Here it is shown that ibuprofen induces a variety of enzymes associated with the oxidative stress response in Bacillus, including catalase, glucose-6-phosphate-dehydrogenase, and aldehyde reductase in a dose-related manner. Furthermore, evidence is presented to show that the expression of cytochrome P450 in Bacillus is associated with a marked depletion in cellular glutathione levels and that it renders these cells considerably more sensitive to oxidant insult. Finally, this work reports that a variety of structurally diverse antioxidants such as ascorbic acid, reduced glutathione, alpha-tocopherol acetate and the artificial antioxidant, butylated hydroxyanisole, all dramatically attenuate the expression of the cytochrome P450BM-3 gene and its repressor, Bm3R1, following ibuprofen treatment. These observations provide the first evidence that the expression of cytochrome P450 genes can lead to increased oxidant sensitivity but can be strongly modulated by dietary and artificial antioxidants, as well as antioxidant enzymes. The important implications of this phenomenon are also discussed.
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Robert Gordon University, School of Applied Sciences, Aberdeen, Scotland, UK.
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D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001410:Bacillus megaterium / Q000201:enzymology*; D001426:Bacterial Proteins; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D007052:Ibuprofen / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D009251:NADPH-Ferrihemoprotein Reductase; D018384:Oxidative Stress
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D001426:Bacterial Proteins; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D009251:NADPH-Ferrihemoprotein Reductase; C052423:flavocytochrome P450 BM3 monoxygenases; D007052:Ibuprofen