Hepatic cytochrome P450 down-regulation during aseptic inflammation in the mouse is interleukin 6 dependent

Hepatology. 2000 Jul;32(1):49-55. doi: 10.1053/jhep.2000.8532.


Expression of cytochromes P450 (CYP) is markedly reduced during inflammatory processes. In vitro studies with hepatocytes have shown that cytokines generated during these processes down-regulate CYP. However, it is not clear to what extent each individual cytokine contributes to the overall reduced expression of the various CYP isoenzymes in vivo. Interleukin 6 (IL-6), a major player during inflammatory processes, is recognized as the most important cytokine modulating the hepatic expression of acute-phase protein (APP) genes. For this reason, we selected the IL-6(-/-) mouse as a model to investigate the role of IL-6 in the down-regulation of hepatic CYP during experimental inflammation. Our results show that the reduction in messenger RNA (mRNA) levels of CYP1A2, CYP2A5, and CYP3A11 during turpentine-induced inflammation was abrogated in IL-6-deficient mice, confirming that IL-6 is an indispensable player for the down-regulation of hepatic CYP during aseptic inflammation. Moreover, the different CYP isoenzymes showed a variable grade of dependence on IL-6, CYP2A5 being the most sensitive one. In the case of CYP2E1, differences between IL-6(-/-) and wild-type mice were no longer maintained after 24 hours, suggesting a delayed, rather than abrogated, CYP down-regulation in the absence of IL-6. As opposed to that, hepatic CYP repression took place in IL-6-deficient mice during lipopolysaccharide (LPS)-mediated inflammation. This contrasting behavior observed for CYP is surprisingly similar to the one seen for extracellular (serum amyloid A, beta-fibrinogen) and intracellular (metallothionein-1) APPs and points to the fact that, in the model of bacterial inflammation (LPS), the effects of IL-6 on CYP down-regulation are likely to be substituted by other cytokines or mediators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Proteins / biosynthesis
  • Animals
  • Cytochrome P-450 Enzyme System / genetics*
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Enzymologic*
  • Inflammation / enzymology*
  • Interleukin-6 / physiology*
  • Isoenzymes / genetics
  • Liver / enzymology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Messenger / analysis


  • Acute-Phase Proteins
  • Interleukin-6
  • Isoenzymes
  • RNA, Messenger
  • Cytochrome P-450 Enzyme System