Reiners J J, Lee J Y, Clift R E, Dudley D T, Myrand S P
Institute of Chemical Toxicology, Wayne State University, Detroit, Michigan 48201, USA.
Mol Pharmacol. 1998 Mar;53(3):438-45. doi: 10.1124/mol.53.3.438.
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 muM were not cytotoxic to cultures of the immortalized human breast epithelial cell line MCF10A. The agent was weakly cytostatic at concentrations of >/=10 microM. In vivo exposure of cultures to </=20 microM 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 muM). Treatment of cultures with PD98059 of >/=1 muM 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 muM) and aryl hydrocarbon receptor (AHR) transformation (IC50 = 1 muM), 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 approximately 190 muM 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.
PD98059 [2-(2'-氨基-3'-甲氧基苯基)-氧杂萘邻酮] 是一种类黄酮，也是丝裂原活化蛋白激酶激酶 (MEK) 的强效抑制剂。浓度≤20 μM的PD98059对永生化人乳腺上皮细胞系MCF10A的培养物无细胞毒性。该药物在浓度≥10 μM时具有弱细胞生长抑制作用。将培养物在体内暴露于≤20 μM的PD98059中2至22小时不会影响细胞外信号调节激酶的总体含量；然而，暴露于PD98059会导致细胞外信号调节激酶的双磷酸化形式迅速丧失（>95%）（IC50 = 1 μM）。在添加2,3,7,8-四氯二苯并对二恶英（TCDD）时或之前长达48小时用≥1 μM的PD98059处理培养物，会以浓度依赖性方式抑制诱导的稳态CYP1A1、CYP1B1和NQO1 mRNA的积累。在添加TCDD之前立即将PD98059添加到大鼠肝细胞溶胶中，通过蔗糖梯度离心和电泳迁移率变动分析测量，可抑制TCDD结合（IC50 = 4 μM）和芳烃受体（AHR）转化（IC50 = 1 μM）。黄酮和黄烷酮是PD98059的两种密切相关的结构类似物，它们抑制TCDD诱导的AHR转化的IC50值与用PD98059获得的值相似。然而，这两种类似物在抑制MEK方面都不如PD98059有效（两者的IC50约为190 μM）。这些结果表明，PD98059是AHR的配体，并且在通常用于抑制MEK和需要MEK激活的信号传导过程的浓度下作为AHR拮抗剂发挥作用。
