P450. CYP arachidonic acid AA 20- P450. EETs 20-HETE 20-HETE P450 P450 R Nelson CYP450 40% CYP. CYP2 55% A2 phospholipase A2 PLA2 CYP2C

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1 285 P arachidonic acid AA AA P450 - EETs HETE EETs 20-HETE P450 P R AA P Nelson CYP450 CYP450 CYP450 40% CYP arachidonic acid AA CYP2 55% A2 phospholipase A2 PLA2 CYP2C P450 cyclooxyge- CYP2C8 nases COXs lipoxygenases LOXs P450 cytochrome P450 CYP AA CYP CYP - epoxyeicosatrienoicacid EETs EET CYP ω- - hydroxyeicosatetraenoic acid HETEs CYP CYP2J CYP2C AA EETs CYP 2C8 2C9 2J2

2 286 2C11 2J3 2C29 2C38 4A11 4F2 4F3 20-HETE Miya A1 4A2 4A3 4A8 2C39 2C40 2J5 2J6 CYP4A CYP4F ta AA 20-HETE ω- 4A10 4A12 4A14 4F14 4A11 4F2 4F3 4F11 4F12 4F15 4F EETs 20-HETE CYP 2C8 Enayetallah C9 2J2 Enayetallah Enayetallah A11 4F2 4F3 4F11 4F12 Lasker Zhang C11 Reem J3 Zeldin Reem A1 4A8 Zhang A2 4A3 Zhang C29 Matsunaga Wang C38 Luo Wang C39 Luo Wang C40 Luo Wang J5 Scarborough Xie J6 Xie A10 4A12 Heng A14 Honeck F14 4F15 4F16 Kikuta Cui EETs seh EETs PPARα II Ca 2 + K + -1 activator protein-1 AP-1 seh 1 2 EETs NF-κB seh DNA 3 EETs seh 62 kda mitogen activated protein kinase MAPK -3 - / phosphatidylinositol 3-kinase-serine /threonine protein kinase PI3K- C 35 kda N 25 kda Akt seh EETs Imig EETs seh EETs soluble epoxide hydrolase seh seh Ephx2 Enayetallah HETE COX HETEs AA LOX α CYP LOX 5-8-

3 HETE CYP 5- enos HETE CYP ω- PI3K p-akt MAPK AMP HETE HETEs AMPK CYP2J3 CYP2J3 /EETs 20-HETE enos IR /IRS-1 PI3K /AKT ATP 20-HETE glucose transporter GLUTs COX 20- E2 20- EETs -1 heme oxygenase-1 I2 Miyata COX GLUT-4 COX COX-1 COX-2 AKT AMPK COX-1 7 COX-2 seh EETs NIT-1 seh 8 seh 4 COX-1 seh NF-κB COX-2 EETs seh EETs CYP2J STZ α EETs 5 EETs 5 6-EET Mustafa EETs 25mM Ephx2 - / - Ca 2 + Ephx2 + / + t-aucb EETs - Ephx2 + / + 25mM EETs Ephx2 - / - Ca 2 + Ephx2 - / - EETs 2 Ephx2 + / + insulin seh receptor IR -1 in- STZ sulin receptor substrate-1 IRS-1 PI3K-Akt seh 6 IRS- seh 1 EETs Xu 6 CYP2J3 /EETs CYP2J3 CYP2J3 db /db HO-1 / Olearczyk Luo 8 seh streptozocin STZ seh t-aucb Ephx2 Ephx2 + / + seh Ohtoshi seh db /db 2 860A 860A db /db seh G860A IRS-1 seh G860A 2

4 288 HETE 20-HETE NADPH OVE26 seh 9 6 ~ 12 CYP4A 10 seh reactive oxygen species ROS seh HETE ROS 20- seh HETE HET HETE ROS 20-HETE CYP4A /20-HETE ROS 20-HETE 20-HETE CYP4A COX HETE CYP4A 25mM 24 Yousif 2006 STZ HETE 100 ~ HETE COX-2 mrna Ca 2 + / Ⅱ STZ 1 db /db 2 20-HETE CYP 4F / -1 Ⅱ COX COX-2 AA AA HETE HET0016 STZ prostaglandins PGs COX-2 Benter COX-2 20-HETE HETE HETE 20- E HETE I2 COX-2 PGs 20-HETE 20-HETE COX CaMKⅡ Ras-GTP CaMKⅡ COX-2 Shanmugam G cpla2 AA AA 20-HETE Ras-GTP 5 COX-2 AA MAPK CaMKⅡ COX-2 AA Ras-GTP 20-HETE Persaud 15 COX-2 NS HETE AA COX-2 AA 1μm /L PGE2 AA 20-HETE PGE mM 1 OVE26 CYP4A 20-HETE γ β-

5 289 Shanmugam 2006 β- 3 Zhang D Ai D Tanaka H et al. DNA methylation of the COX-2 promoter of soluble epoxide hydrolase silences its expression Heitmeier by an SP-1-dependen mechanism. Biochim Biophys Acta ~ Hao CM Breyer MD. Physiological regulation of prostaglandins in the kidney. Annu Rev Physiol inos /NO COX-2 PGE2 ~ 377. COX- 5 Yeung-Yam-Wah V Lee AK Tse FW et al. Arachidonic 2 PGE2 acid stimulates extracellular Ca 2 + entry in rat pancreatic β- COX-2 NS-398 cells via activation of the noncapacitative arachidonate-regulated Ca 2 + ARC channels. Cell Calcium ~ PGE2 NS- 398 Papadimitriou COX-2 6 Xu X Zhao CX Wang L et al. Increased CYP2J3 expression 20-HETE reduces insulin resistance in fructose-treated rats and db /db mice. Diabetes ~ Nicolai A Li M Kim DH et al. Heme oxygenase-1 induction remodels adipose tissue and improves insulin sensitivity P450 EETs in obesity-induced diabetic rats. Hypertension Ca 2 + β 508 ~ 515. IR /IRS-1 PI3K /AKT 8 Luo P Chang HH Zhou Y et al. Inhibition or deletion of HO-1 / /GLUT-4 soluble epoxide hydrolase prevents hyperglycemia promotes EETs seh insulin secretion and reduces islet apoptosis. J Pharmaol seh Exp Ther ~ 438. seh β 9 Forbes JM Coughlan MT Cooper ME. Oxidative stress as a 20-HETE CaMK major culprit in kidney disease in diabetes. Diabetes ~ Ⅱ /Ras-GTPase 10 Randriamboavonjy V Pistrosch F Bolck B et al. Platelet ROS sarcoplasmic endoplasmic reticulum Ca 2 + -ATPase and mucalpain activity are altered in type 2 diabetes mellitus and EETs restored by rosiglitazone. Circulation ~ 60. seh 11 Barbosa-Sicard E Fromel T Keseru B et al. Inhibition of the soluble epoxide hydrolase by tyrosine nitration. J Biol CYP4A CYP4F 20-HETE Chem ~ HETE 12 Yousif MH Benter IF Dunn KM et al. Role of 20- hydroxyeicosatetraenoic acid in altering vascular reactivity in diabetes. Auton Autacoid Pharmacol ~ Eid AA Gorin Y Fagg BM et al. Mechanisms of podocyte injury in diabetes role of cytochrome P450 and NAD- PH oxidases. Diatetes ~ Liu JY Li N Yang J et al. Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated 1 Ai D Fu Y Guo D et al. Angiotensin II up-regulates soluble cardiovascular events. Proc Natl Acad Sci USA epoxide hydrolase in vascular endothelium in vitro and in ~ vivo. Proc Natl Acad Sci USA ~ Persaud SJ Muller D Belin VD et al. The role of 2 Ai D Shyy JY Zhu Y. Linking an insect enzyme to hypertension angiotensinii arachidonic acid and its metabolites in insulin secretion epoxide hydrolase interactions. Kidney from human islets of langerhans. Diabetes Int ~ ~ 203.