Elsevier

Toxicology

Volumes 181–182, 27 December 2002, Pages 207-210
Toxicology

Mechanisms of cytochrome P450 regulation by inflammatory mediators

https://doi.org/10.1016/S0300-483X(02)00283-4Get rights and content

Abstract

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-κB 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.

Introduction

Infectious or inflammatory stimuli cause decreased catalytic activities of hepatic cytochrome P450 enzymes in experimental animals and in man, which can cause dose-dependent drug toxicity associated with impaired in vivo drug clearance (Morgan, 1997). In most cases, the decreased catalytic activity is accompanied or preceded by decreases in hepatic levels of the corresponding P450 mRNAs and proteins (Morgan, 1997).

The above effects of in vivo inflammatory stimuli on individual P450 enzymes can generally be recapitulated by incubation of cultured rat or human hepatocytes with inflammatory cytokines or interferons (Morgan, 1997). Thus these agents, which also regulate the expression of hepatic acute phase proteins and nitric oxide synthase (NOS)-2 (Liaudet et al., 2000), play a major role in regulation of P450 expression and activity in inflammatory disease states. However, as reviewed previously (Morgan, 2001) receptors for bacterial lipopolysaccharide (LPS) are present on hepatocytes, such that this agent may act directly on hepatocytes to regulate P450s during bacterial sepsis.

Section snippets

Transcriptional and post-transcriptional regulation of P450 mRNAs

There is evidence for both transcriptional and post-transcriptional down-regulation of P450 mRNAs by inflammatory stimuli. We found that treatment of rats with LPS or with the sterile irritant turpentine caused almost complete inhibition of CYP2C11 gene transcription, measured by run-on assays, 24 h after treatment (Wright and Morgan, 1990). However, even an instantaneous blockade of transcription of CYP2C11 does not account for the rapid decline of CYP2C11 mRNA in rats treated with LPS, in

Role of nitric oxide in P450 down-regulation

As mentioned previously, inflammatory cytokines cause the induction of NOS2 in hepatocytes, which leads to a massive increase in NO production in the liver (Liaudet et al., 2000). NO can bind to P450 enzymes, causing inhibition both by reversible heme ligation and by an irreversible mechanism (Wink et al., 1993). Reaction of NO in the cell with superoxide anion can produce peroxynitrite, which is capable of modifying proteins by tyrosine nitration, S-nitrosylation or thiol oxidation (Liaudet et

Acknowledgements

Supported by grants GM53093 and GM46897 from the National Institutes of Health.

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