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THE MITOGEN-ACTIVATED PROTEIN KINASE KINASE (MEK) INHIBITOR PD98059 ELEVATES PRIMARY CULTURED RAT HEPATOCYTE GLUTATHIONE LEVELS INDEPENDENT OF INHIBITING MEK

Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan

The antioxidant activity of flavonoids, directly through scavenging oxidizing species and indirectly through modulating drug-metabolizing enzyme activities, is associated with chemopreventive and chemotherapeutic effects. However, little published information is available concerning the effect of flavonoids on glutathione (GSH) homeostasis. We previously demonstrated that PD98059 (2'-amino-3'-methoxyflavone), a flavone derivative and selective mitogen-activated protein kinase kinase (MEK) 1 inhibitor, enhanced the insulin-mediated increase in GSH levels (J Pharmacol Exp Ther 311:99–108). To determine whether the PD98059-mediated increase in GSH levels was associated with MEK inhibition, primary cultured rat hepatocytes were treated with PD98059, the MEK inhibitor U0126, which is not a flavone derivative, or flavone. PD98059 increased GSH levels in a concentration-dependent manner in hepatocytes cultured in the presence or absence of insulin. In contrast, GSH levels were not affected by U0126 at concentrations sufficient to inhibit insulin-mediated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Flavone, however, markedly increased GSH levels without inhibition of ERK1/2 phosphorylation. The concentration of GSH in the culture medium was also elevated by PD98059 or flavone, suggesting that the cellular GSH elevation could not be accounted for by the inhibition of GSH efflux into medium. Interestingly, PD98059 and flavone increased cellular cysteine levels, which may be responsible for the PD98059- and flavone-mediated elevation of GSH levels. These results provide evidence that PD98059 and flavone produce dramatic changes in GSH homeostasis in hepatocytes, through a mechanism(s) unrelated to MEK inhibition. Moreover, the current study implies that flavonoid-induced chemopreventive and chemotherapeutic effects may be mediated by regulation of redox state through the stimulation of GSH synthesis.