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Inhibitors of cytochrome P450 suppress tumor necrosis factor production
G Fantuzzi1, L Cantoni, M Sironi
1Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Abstract:
We tested the effect of different inhibitors of cytochrome P450 on tumor necrosis factor (TNF) production. Metyrapone and SKF525A (100 and 50 mg/kg, ip, respectively) suppressed serum TNF induced by cotreatment with endotoxin (LPS), (2.5 micrograms/mouse). Inhibition was independent of endogenous corticosteroids since it was also observed in adrenalectomized mice. In vitro production of TNF by endotoxin-stimulated human monocytes was also inhibited by metyrapone and SKF525A. Since lipoxygenase (LO) inhibitors also block TNF production and metyrapone was reported to inhibit LO, we suggest that inhibition by metyrapone and SKF525A might be due to inhibition of either LO or a cytochrome P450 implicated in the oxidation of endogenous substrates involved in the inflammatory response.
Insights
Cytochrome P450 inhibitors, metyrapone and SKF525A, significantly reduced tumor necrosis factor (TNF) production in vivo and in vitro. This inhibition occurred independently of corticosteroids and may involve lipoxygenase pathways.
Area of Science:
- Immunology
- Pharmacology
- Biochemistry
Background:
- Tumor necrosis factor (TNF) is a key inflammatory cytokine.
- Cytochrome P450 enzymes play roles in various biological processes, including inflammation.
- Understanding modulators of TNF production is crucial for inflammatory disease research.
Purpose of the Study:
- To investigate the effect of cytochrome P450 inhibitors on TNF production.
- To determine if TNF inhibition by these agents is corticosteroid-dependent.
- To explore potential mechanisms, including lipoxygenase (LO) involvement.
Main Methods:
- Administration of metyrapone and SKF525A to mice treated with lipopolysaccharide (LPS).
- Measurement of serum TNF levels.
- In vitro experiments using LPS-stimulated human monocytes and inhibitor treatments.
Main Results:
- Metyrapone and SKF525A suppressed LPS-induced serum TNF in mice.
- Inhibition was observed in both intact and adrenalectomized mice, indicating corticosteroid independence.
- Both inhibitors reduced TNF production by LPS-stimulated human monocytes in vitro.
Conclusions:
- Cytochrome P450 inhibitors metyrapone and SKF525A effectively reduce TNF production.
- The inhibitory mechanism is not mediated by endogenous corticosteroids.
- Inhibition may be linked to lipoxygenase pathways or specific cytochrome P450 enzymes involved in inflammatory substrate oxidation.