Activation of phosphatidylinositol 3-kinase by oxidative stress leads to the induction of microsomal epoxide hydrolase in H4IIE cells.
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.
Kang
K W
KW
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Sillim-dong, Kwanak-gu, 151-742, Seoul, South Korea.
Ryu
J H
JH
Kim
S G
SG
D000603:Amino Acids, Sulfur / Q000172:deficiency; D000818:Animals; D004789:Enzyme Activation; D004790:Enzyme Induction; D004851:Epoxide Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D008114:Liver Neoplasms, Experimental / Q000201:enzymology; D018384:Oxidative Stress / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D014407:Tumor Cells, Cultured
D000603:Amino Acids, Sulfur; D004851:Epoxide Hydrolases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; C494920:Akt1 protein, rat