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Depression of constitutive murine cytochromes P450 by staphylococcal enterotoxin B
S I Shedlofsky1, R T Tosheva, J A Snawder
1Department of Veterans Affairs Medical Center/University of Kentucky, Lexington, KY 40511, USA. Shedlofsky.Steve@Lexington.VA.Gov
Abstract:
Most in vivo studies demonstrating decreased activities of hepatic cytochromes P450 with inflammation have used Gram-negative bacterial lipopolysaccharide (LPS) as the inflammatory stimulant. But products of Gram-positive bacteria, such as staphylococcal enterotoxin B (SEB), also stimulate inflammatory mediators, albeit with a different pattern than LPS. Therefore, effects of SEB on the regulation of murine constitutive P450s were determined in this study and compared with those of LPS. LPS-responsive C3H/HeN and LPS-unresponsive C3H/HeJ mice were injected with either LPS (0.5 mg/kg) or SEB (0.66 to 6.6 mg/kg), and hepatic cytochromes P450 and serum tumor necrosis factor-alpha, interleukin-6, nitrate/nitrite, and serum amyloid A concentrations were determined up to 24 hr. HeJ mice were generally less responsive than HeN mice to both stimuli, with lower cytokine, nitrate/nitrite, and serum amyloid A responses. However, in both mouse strains SEB caused more prolonged cytokine, higher nitrate/nitrite, and lower serum amyloid A concentrations than LPS. Despite these differences, in HeN mice, after both SEB and LPS administration, total P450 concentrations were equally depressed by 40%. Both SEB and LPS depressed CYP1A1 and 1A2 microsomal protein concentrations by 45 and 30%, respectively; CYP2E1 by 64%; and CYP3A by 70%. There was comparable inhibition of enzymatic activities. In HeJ mice, SEB was only slightly more effective in depressing P450s than LPS, as might be expected. These data showed that the Gram-positive bacterial inflammatory stimulant SEB caused effects on murine hepatic cytochromes P450 similar to those of LPS, even though the pattern of inflammatory mediators induced after SEB exposure was different.
Insights
Staphylococcal enterotoxin B (SEB), a Gram-positive bacterial product, similarly decreases hepatic cytochrome P450 activity as lipopolysaccharide (LPS) in mice. This occurs despite SEB inducing a different inflammatory mediator profile than LPS.
Area of Science:
- Pharmacology and Toxicology
- Immunology
- Biochemistry
Background:
- Inflammation significantly impacts drug metabolism, primarily by reducing hepatic cytochrome P450 (CYP450) enzyme activity.
- Most studies utilize Gram-negative bacterial lipopolysaccharide (LPS) to induce inflammation and observe CYP450 downregulation.
- Gram-positive bacterial products, like staphylococcal enterotoxin B (SEB), also trigger inflammatory responses, but their effects on CYP450 are less understood.
Purpose of the Study:
- To investigate the impact of staphylococcal enterotoxin B (SEB) on murine hepatic CYP450 regulation.
- To compare the effects of SEB with those of lipopolysaccharide (LPS) on CYP450 activity and inflammatory markers.
- To elucidate the role of bacterial components from different sources in modulating drug-metabolizing enzymes during inflammation.
Main Methods:
- Administration of LPS or SEB to LPS-responsive (C3H/HeN) and LPS-unresponsive (C3H/HeJ) mice.
- Measurement of hepatic CYP450 concentrations and activities, alongside serum levels of tumor necrosis factor-alpha, interleukin-6, nitrate/nitrite, and serum amyloid A.
- Comparative analysis of inflammatory mediator profiles and their correlation with CYP450 changes induced by SEB and LPS.
Main Results:
- Both SEB and LPS equally reduced total hepatic CYP450 concentrations by 40% in LPS-responsive mice.
- Specific CYP isoforms (CYP1A1, 1A2, 2E1, 3A) and their activities were significantly inhibited by both SEB and LPS.
- SEB induced more prolonged cytokine elevation, higher nitrate/nitrite levels, and lower serum amyloid A compared to LPS, with differences noted between mouse strains.
Conclusions:
- Gram-positive bacterial stimulant SEB exerts similar inhibitory effects on murine hepatic CYP450s as Gram-negative bacterial stimulant LPS.
- The observed downregulation of CYP450 by SEB occurs despite a distinct inflammatory mediator response pattern compared to LPS.
- These findings highlight that diverse bacterial inflammatory triggers can converge to suppress key drug-metabolizing enzymes.