Sustained Aryl Hydrocarbon Receptor Activity Attenuates Liver Regeneration

• Published in: Molecular pharmacology 2006-07, Vol.70 (1), p.163-170
• Main Authors: Mitchell, Kristen A, Lockhart, Courtney A, Huang, Gengming, Elferink, Cornelis J
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Cell Cycle Proteins - metabolism; Cell Proliferation - drug effects; Cells, Cultured; Cyclin-Dependent Kinase 2 - metabolism; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A1 - metabolism; Environmental Pollutants - toxicity; Female; G1 Phase - drug effects; Gene Expression - drug effects; Hepatectomy; Immunoprecipitation; Interleukin-6 - biosynthesis; Liver - drug effects; Liver - metabolism; Liver - physiopathology; Liver Regeneration - drug effects; Liver Regeneration - physiology; Mice; Mice, Inbred C57BL; Polychlorinated Dibenzodioxins - toxicity; Receptors, Aryl Hydrocarbon - agonists; Receptors, Aryl Hydrocarbon - physiology; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.106.023465

In hepatocyte-derived cell lines, either loss of aryl hydrocarbon receptor (AhR) function or treatment with a persistent AhR agonist such as 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) can disrupt G 1 phase cell cycle progression. The present study used liver regeneration to explore mechanistically how AhR activity modulates hepatocyte proliferation in vivo. Treatment of mice with 20 μg/kg TCDD 1 day before 70% partial hepatectomy (PH) resulted in a 50 to 75% suppression in liver regeneration. Impaired proliferation was not associated with changes in levels of interleukin-6 or tumor necrosis factor-α, which prime quiescent hepatocytes to enter G 1 phase. In fact, administration of TCDD 12 h after PH, a period well beyond the priming phase, still induced the G 1 arrest. Decreased proliferation in TCDD-treated mice correlated with reduced cyclin-dependent kinase-2 (CDK2) activity, a pivotal regulator of G 1 /S phase transition. In contrast to observations made in cell culture, suppressed CDK2 activity was not strictly associated with increased binding of the CDK2 inhibitors p21 Cip1 or p27 Kip1 . However, TCDD decreased levels of cyclin E binding to CDK2, despite normal cyclin E expression. The evidence also suggests that TCDD-induced hepatic growth arrest depends upon sustained AhR activity because transient AhR activation in response to endogenous queues failed to suppress the regenerative response. These findings establish a functional role for the AhR in regulating normal cell cycle control during liver regeneration.