Suppression of cell cycle progression by flavonoids: dependence on the aryl hydrocarbon receptor

Some flavonoids are ligands of the aryl hydrocarbon receptor (AHR) and caus e cell cycle arrest. The dependency of the cytostatic effects of five flavo noids (flavone, alpha-naphthoflavone, apigenin, 3'-methoxy-4'-nitroflavone and 2'-amino-3'-methoxyflavone) on a functional AHR was examined in AHR-con taining rat hepatoma 5L cells and an AHR-deficient cell line (BP8) derived from the 5L line. The potent AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was cytostatic to the 5L line due to the induction of a G(1) arrest and dramatically elevated steady-state levels of CYP1A1 mRNA, TCDD affecte d neither the proliferation nor CYP1A1 mRNA contents of BP8 cells. With the exception of apigenin, the flavonoids under study induced G1 arrest in bot h 5L and BP8 cells when used at concentrations at which they functioned as AHR agonists, but not antagonists. Apigenin-treated 5L and BP8 cultures pri marily arrested in G(2)/M. The AHR-containing murine hepatoma cell line 1c1 c7 arrested following exposure to AHR agonist concentrations of flavone and alpha-naphthoflavone, but not TCDD, Unlike the G(1) arrest observed in 5L cultures, the latter two flavonoids caused principally G(2)/M arrest in 1c1 c7 cells. These studies demonstrate that the cytostatic activities of flavo noids do not require the AHR and the site of checkpoint arrest with a speci fic flavonoid can vary with cell type.