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Vol. 53, Issue 3, 438-445, March 1998
Institute of Chemical Toxicology, Wayne State University, Detroit,
Michigan 48201 (J.J.R., J-Y.L., R.E.C., S.P.M.), and
Department of Cell
Biology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert
Company, Ann Arbor, Michigan 48105 (D.T.D.)
PD98059 [2-(2
-amino-3-methoxyphenyl)-oxanaphthalen-4-one] is a
flavonoid and a potent inhibitor of mitogen-activated protein kinase
kinase (MEK). Concentrations of PD98059 of 
20 µM were not cytotoxic to cultures of the immortalized human breast epithelial cell line MCF10A. The agent was weakly cytostatic at concentrations of
10 µM. In vivo exposure of cultures to
20 µM PD98059 for 2-22 hr did not affect overall
extracellular signal-regulated kinase contents; however, exposure to
PD98059 resulted in a rapid loss (>95%) of the dually phosphorylated
forms of extracellular signal-regulated kinase (IC50 = 1 µM). Treatment of cultures with PD98059 of 1
µM either at the time of addition or up to 48 hr before
the addition of 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD) suppressed in a concentration-dependent manner the accumulation of induced steady state CYP1A1, CYP1B1, and NQO1 mRNAs. The addition of
PD98059 to rat liver cytosol just before the addition of TCDD suppressed TCDD binding (IC50 = 4 µM) and
aryl hydrocarbon receptor (AHR) transformation (IC50 = 1 µM), as measured by sucrose gradient centrifugation and
electrophoretic mobility shift assays. Flavone and flavanone, two
closely related structural analogs of PD98059, inhibited AHR
transformation by TCDD with IC50 values similar to that
obtained with PD98059. However, neither analog was as potent as PD98059
in inhibiting MEK (IC50 ~ 190 µM for both). These results suggest that PD98059 is a ligand for the AHR and functions as an AHR antagonist at concentrations commonly used to
inhibit MEK and signaling processes that entail MEK activation.
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