Related Experiment Videos
Evidence for nitric oxide participation in down-regulation of CYP2B1/2 gene expression at the pretranslational level
O G Khatsenko1, A R Boobis, S S Gross
1The William Harvey Research Institute, St. Bartholomew's Medical College, London, UK. okhatsen@uci.edu
Abstract:
Septic or inflammatory stimuli suppress drug metabolism by cytochrome P-450 in the liver, presumably at the pretranslational level. We have shown previously that nitric oxide is responsible at least in part for the inhibition by bacterial lipopolysaccharide of phenobarbital-induced CYP2B1/2 activity in vivo. This was attributed to the interaction of nitric oxide with heme in the active-center of cytochrome P450, leading to enzyme inactivation. Here, we report that endogeneous nitric oxide also contributes to LPS-induced suppression of CYP2B1/2 in vivo by down-regulating the expression of CYP2B1/2 protein and mRNA.
Insights
Septic stimuli, like lipopolysaccharide (LPS), suppress drug metabolism by reducing cytochrome P450 (CYP) enzyme expression. Endogenous nitric oxide plays a key role in this LPS-induced suppression.
Area of Science:
- Biochemistry
- Pharmacology
- Immunology
Background:
- Sepsis and inflammation suppress liver drug metabolism via cytochrome P450 (CYP) enzymes.
- Nitric oxide (NO) has been implicated in inhibiting CYP activity, potentially through direct heme interaction.
- Previous work suggested NO's role in lipopolysaccharide (LPS)-induced suppression of phenobarbital-induced CYP2B1/2 activity.
Purpose of the Study:
- To investigate the role of endogenous nitric oxide in the suppression of CYP2B1/2 expression during LPS-induced inflammation.
- To determine if NO contributes to the down-regulation of CYP2B1/2 protein and mRNA levels in vivo.
Main Methods:
- In vivo studies using animal models exposed to lipopolysaccharide (LPS).
- Measurement of CYP2B1/2 enzyme activity.
- Quantification of CYP2B1/2 protein and mRNA levels.
- Assessment of the role of endogenous nitric oxide.
Main Results:
- Endogenous nitric oxide contributes to the suppression of CYP2B1/2 activity in vivo during LPS challenge.
- LPS-induced suppression of CYP2B1/2 involves the down-regulation of both CYP2B1/2 protein and mRNA expression.
- Nitric oxide mediates the reduction in CYP2B1/2 expression at the pretranslational level.
Conclusions:
- Endogenous nitric oxide is a significant mediator of LPS-induced suppression of drug metabolism by down-regulating CYP2B1/2 expression.
- This study elucidates a molecular mechanism involving nitric oxide in the inflammatory suppression of drug-metabolizing enzymes.
- Findings highlight the complex interplay between inflammatory signaling and hepatic drug metabolism.