Cytochrome P4501A1 Promotes G₁ Phase Cell Cycle Progression by Controlling Aryl Hydrocarbon Receptor Activity

The aryl hydrocarbon receptor (AhR) transcription factor is increasingly recognized as functioning in cell cycle control. Several recent reports have shown that AhR activity in the absence of exogenous agonists or presence of the prototypical ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin can affect G ₁ phase progression in cultured cells. Serum release of serum-starved (G₀) 5L rat hepatoma cells triggers transient AhR activation and P4501A1 protein expression concomitant with the G ₀/G₁-to-S phase transition. In contrast, sustained AhR activation in response to TCDD treatment increases p27^Kip expression in addition to P4501A1, resulting in G₁ phase cell cycle arrest. Treating serum-released 5L cells with the alkyne metabolism-based P4501A1 inhibitor 1-(1-propynyl)pyrene results in prolonged AhR activation, enhanced p27^Kip expression, and G₁ phase arrest after serum release. The data are consistent with a cell cycle role for P4501A1 because they show that P4501A1 negatively regulates the duration of AhR action through the metabolic removal of the receptor agonist, thereby preventing AhR-mediated G₁ phase arrest.