Down‐regulation of human CYP3A4 by the inflammatory signal interleukin 6: molecular mechanism and transcription factors involved

Abstract

The hepatic drug-metabolizing cytochrome P-450 (CYP) enzymes are down-regulated during inflammation. In vitro studies with hepatocytes have shown that the cytokines released during inflammatory responses are largely responsible for this CYP repression. However, the signaling pathways and the cytokine-activated factors involved remain to be properly identified. Our research has focused on the negative regulation of CYP3A4 (the major drug-metabolizing human CYP) by interleukin 6 (IL-6) (the principal regulator of the hepatic acute-phase response). CYP3A4 down-regulation by IL-6 requires activation of the glycoprotein receptor gp130; however, it does not proceed through the JAK/STAT pathway, as demonstrated by the overexpression of a dominant-negative STAT3 factor by means of an adenoviral vector. The involvement of IL-6-activated kinases such as extracellular signal-regulated kinase ERK1/2 or p38 is also unlikely, as evidenced by the use of specific chemical inhibitors. It is noteworthy that IL-6 caused a moderated induction in the mRNA of the transcription factor C/EBPbeta (CCAAT-enhancer binding protein beta) and a marked increase in the translation of C/EBPbeta-LIP, a 20-kDa C/EBPbeta isoform lacking a transactivation domain. Adenovirus-mediated expression of C/EBPbeta-LIP caused a dose-dependent repression of CYP3A4 mRNA, whereas overexpression C/EBPalpha and C/EBPb-LAP (35 kDa) caused a significant induction. Our results support the idea that IL-6 down-regulates CYP3A4 through translational induction of C/EBPbeta-LIP, which competes with and antagonizes constitutive C/EBP transactivators. From a clinical point of view, these findings could be relevant in the development of therapeutic cytokines with a less repressive effect on hepatic drug-metabolizing enzymes.

Regulation of Drug-Metabolizing Enzymes and Transporters in Infection, Inflammation, and Cancer

“…3). Our laboratory and others have also demonstrated transcriptional suppression of P450s by cytokines using various reporter gene constructs in primary hepatocytes and hepatoma cells (Chen et al, 1995;Jover et al, 2002;Aitken et al, 2006). Therefore, transcriptional suppression is clearly an important contributor to P450 mRNA down-regulation.…”

Gene Expression Profile at the G1/S Transition of Liver Regeneration after Partial Hepatectomy in Mice

“…Recent studies have found that several different liver-enriched transcription factors including HNF-1, HNF-3, HNF-4, and C/EBP β, and the more ubiquitously expressed factors Sp1, GABP β, and NF2d9 are responsible for governing the transcription of P450 genes. 27 In addition, cytochrome P450 and its dependent activities have been shown to be regulated by the availability of cellular heme. Consistent with these reports seven out of ten Cytochrome 450 enzymes observed in our expression profile were downregulated at the G 1 /S boundary of liver regeneration.…”

Decreased Expression of Cytochromes P450 1A2, 2E1, and 3A4 and Drug Transporters Na+-Taurocholate-Cotransporting Polypeptide, Organic Cation Transporter 1, and Organic Anion-Transporting Peptide-C Correlates with the Progression of Liver Fibrosis in Chronic Hepatitis C Patients

“…In our study population, up-regulation of TNF-␣ was consistent overall with the studies by Asselah et al (2005), but IL-6 mRNAs were below the limit of detection in many subjects. IL-6 has been shown to down-regulate CYP1A1, CYP1A2, and CYP3A4 in human hepatoma cells (Fukuda et al, 1992) and to down-regulate CYP2E1 (Hakkola et al, 2003) and CYP3A4 (Jover et al, 2002). Abdel-Razzak et al (1993) showed that IL-6, IL-1␤, and TNF-␣ down-regulated expression of human CYP1A1, 1A2, and 3A in adult human hepatocytes in primary culture.…”