Mechanisms of cytochrome P450 regulation by inflammatory mediators.

Hepatic levels of cytochrome P450 enzymes and their mRNAs are reduced in models of inflammation or infection. The contributions of transcriptional versus post-transcriptional mechanisms to this decline are poorly understood. The transcription of CYP2C11 is rapidly suppressed by administration of bacterial endotoxin (lipopolysaccharide, LPS) to rats, consistent with the finding that the CYP2C11 promoter contains a negative NF-kappa B response element that confers down-regulation of a linked reporter gene by cytokines. Nitric oxide has been proposed to be a mediator of inflammatory suppression of P450 expression, but reports from different laboratories have disagreed on this subject. Recently, we found that LPS suppresses the expression of CYP2B1 by both pre-translational and post-translational mechanisms in rat hepatocytes, the latter being NO-dependent and occurring only at high concentrations of LPS. Studies were conducted in control and NOS2-null mice to determine the contributions of these different mechanisms to CYP2B suppression in vivo.