Importance of hepatic induction of constitutive androstane receptor and other transcription factors that regulate xenobiotic metabolism and transport.

Aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor-alpha (PPARalpha), and nuclear factor-E2-related factor 2 (Nrf2) are transcription factors that mediate xenobiotic induction of biotransformation enzymes and transporters. The purpose of this study was to determine the tissue distribution and xenobiotic induction of these transcription factors and their associated target genes in mice. Many of these transcription factors were most highly expressed in extrahepatic tissues. CAR expression in female liver was twice that in male liver. This corresponded with greater induction of the CAR target genes Cyp2b10 and multidrug resistance-associated protein (Mrp) 4 by the CAR activator 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in female liver than in male liver. Mice were treated with xenobiotic activators of AhR, CAR, PXR, PPARalpha, or Nrf2 and their associated marker genes were highly induced in liver by these xenobiotic activators. Transcription factor target gene induction occurred with minimal induction of their associated transcription factors. CAR expression was induced by the AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), leading to increased basal expression of Cyp2b10 mRNA and enhanced induction of Cyp2b10 by TCPOBOP. Mrp2, 3, and 4 induction was augmented by cotreatment with TCDD and TCPOBOP compared with treatment with either compound alone. These studies illustrate CAR induction by TCDD in mice, indicating that AhR may transcriptionally regulate CAR and thus enhance induction of key metabolism and transporter genes by the CAR activator TCPOBOP. Collectively, these studies illustrate the fact that some xenobiotic inducers may elicit their response through mechanisms involving transcription factor regulation.