TY - JOUR T1 - Gene Regulation of CYP4F11 in Human Keratinocyte HaCaT Cells JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.109.029025 SP - dmd.109.029025 AU - Ying Wang AU - Jordan C Bell AU - Diane S Keeney AU - Henry W. Strobel Y1 - 2009/01/01 UR - http://dmd.aspetjournals.org/content/early/2009/10/19/dmd.109.029025.abstract N2 - Mechanisms regulating CYP4F genes remain under investigation, although characterization of CYP4F regulatory modalities would facilitate the discovery of new drug targets. This present study shows that all-trans and 9-cis retinoic acids can inhibit CYP4F11 expression in human keratinocyte-derived HaCaT cells. Transrepression of many genes by retinoic acids is mediated by interactions between retinoid receptors and the AP-1 complex. Pro-inflammatory cytokines TNFα and IL-1β, which can activate the AP-1 complex, induce CYP4F11 transcription in HaCaT cells. The JNK-specific inhibitor SP600125 blocked the induction of CYP4F11 by both cytokines, indicating involvement of the JNK pathway. Furthermore, TNFα failed to induce CYP4F11 transcription when HaCaT cells were pre-incubated with retinoic acids. Retinoic acids are ligands for nuclear receptors RARs (the retinoic acid receptors) and RXRs (the retinoid X receptors). The RXR agonist LG268 greatly induced CYP4F11 transcription, whereas the RAR agonist TTNPB markedly inhibited CYP4F11 transcription, indicating that down-regulation of CYP4F11 transcription by retinoic acid is mediated by RARs and may also be related to ligand competition for RXR receptors. Thus, the CYP4F11 gene is positively regulated by multiple signaling pathways in HaCaT keratinocytes including RXR and JNK signaling pathways.The American Society for Pharmacology and Experimental Therapeutics ER -