Nmr-based Metabonomic Studies Of Mouse Induced Sulprostone, An Agonist Of EP1/3

On the COX pathway of arachidonic acid metabolism, prostaglandin E2(PGE2), a widely distributed substance in the body, regulates signal transduction pathways through the specific combination with receptor EP1, EP2, EP3and EP4respectively. And it is also involved in many important physiological and pathological processes. Sulprostone, as an analogue of PGE2, plays its biological functions through the activation of EP1and EP3, but its metabolic foundation is still unclear. Nuclear Magnetic Resonance (NMR)-based metabonomic method developed in recent years provided some new ideas for the effects of mouse induced by sulprostone. In this dissertation, the1H NMR spectroscopic techniques in conjunction with multivariate data analysis methods were employed to understand the sulprostone-induced metabonomic changes in mouse.The results showed that following32days of treatment, sulprostone with middle (0.1mg/Kg) and high (1mg/Kg) dose caused significant elevation of acetate, succinate, NADP+, NAD+, UDP, UMP, AMP and bile acids together with the level reduction of glycogen, glucose, uridine, xanthine, hypoxanthine and inosine in liver. We also found that mice dosed with O.lmg/Kg leaded elevation of lipid,3-HB, and lactate together with reduction of fumarate, whereas the high dose group (1mg/Kg) showed elevation of glutamate, GSSG, together with reduction of tyrosine and phenylalanine. Three week recovery after sulprostone treatment the high dose group still showed significant elevation of uridine and choline, together with reduction of GSSG in live. These indicated that sulprostone caused the disturbance of glucose and lipid metabolisms, the changes in nucleic acid and protein metabolites in liver. Sulprostone also had effect on liver function with a dose-dependent manner. The clinical chemistry and multivariate data analysis also showed that the middle and high dose group of sulprostone may have had impacts on the functions and metabolism of kidney. Furthermore, serum multivariate data anlysis indicated that there was no significant effect caused by sulprostone. It could be inferred that such changes was maintained by homeostasis.These results provided more details for our understanding of the effect of PGE2-EP1/3signaling pathways in the mouse, especially in the metabolic aspects.