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Carcinogenesis, Vol. 20, No. 8, 1561-1566, August 1999
© 1999 Oxford University Press

Carcinogenesis

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

John J. Reiners, Jr1, Russell Clift and Patricia Mathieu

Institute of Chemical Toxicology, Wayne State University, 2727 Second Avenue, Detroit, MI 48201, USA

Some flavonoids are ligands of the aryl hydrocarbon receptor (AHR) and cause cell cycle arrest. The dependency of the cytostatic effects of five flavonoids (flavone, {alpha}-naphthoflavone, apigenin, 3'-methoxy-4'-nitroflavone and 2'-amino-3'-methoxyflavone) on a functional AHR was examined in AHR-containing 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 G1 arrest and dramatically elevated steady-state levels of CYP1A1 mRNA. TCDD affected neither the proliferation nor CYP1A1 mRNA contents of BP8 cells. With the exception of apigenin, the flavonoids under study induced G1 arrest in both 5L and BP8 cells when used at concentrations at which they functioned as AHR agonists, but not antagonists. Apigenin-treated 5L and BP8 cultures primarily arrested in G2/M. The AHR-containing murine hepatoma cell line 1c1c7 arrested following exposure to AHR agonist concentrations of flavone and {alpha}-naphthoflavone, but not TCDD. Unlike the G1 arrest observed in 5L cultures, the latter two flavonoids caused principally G2/M arrest in 1c1c7 cells. These studies demonstrate that the cytostatic activities of flavonoids do not require the AHR and the site of checkpoint arrest with a specific flavonoid can vary with cell type.

Abbreviations: {alpha}-NF, {alpha}-naphthoflavone or 7,8-benzoflavone; AHR, aryl hydrocarbon receptor; DMSO, dimethylsulfoxide; ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; PBS, phosphate-buffered saline; PD98059, 2'-amino-3'-methoxyflavone; PD168641, 3'-methoxy-4'-nitroflavone; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin

1 To whom correspondence should be addressedEmail: john.reiners.jr{at}wayne.edu


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