Kang_2001_Toxicol.Lett_121_191

We have shown that PI3-kinase played an essential role in the ARE-mediated rGSTA2 induction by oxidative stress following SAAD (Mol. Pharmacol. 58 (2000) 1017). Microsomal epoxide hydrolase (mEH), which detoxifies a variety of epoxide intermediates produced from various xenobiotics, is inducible by oxidative stress. In the present study, we studied whether sulfur amino acid deprivation (SAAD) activated phosphatidylinositol 3-kinase (PI3-kinase)/Akt and induced mEH in H4IIE cells. The role of PI3-kinase activation on the mEH induction by SAAD was also investigated. PI3-kinase was activated from 10 min through 12 h after SAAD, the activity of which returned to control level at 24 h. The activation of PI3-kinase led to increases in the activity of Akt at the same time points. Northern and Western blot analyses revealed that the mEH mRNA level was four-fold increased at 48 h, which accompanied the induction of mEH protein. Wortmannin or LY294002, PI3-kinase inhibitors, completely inhibited the increases in mEH mRNA and protein by SAAD. These results demonstrated that SAAD activated the PI3-kinase/Akt pathway at early stages and induced mEH, presumably as an adaptive response, and that the PI3-kinase/Akt pathway played a crucial role in the induction of mEH.