The regulatory mechanism involved in the prostaglandin E disposition in carbon tetrachloride-induced liver injury.

Prostaglandin E (PGE) exhibits hepatoprotective effects against various types of liver injury. However, there is little information on the disposition of endogenous PGE during liver injury. In the present study, we attempted to elucidate the mechanism involved in regulating PGE distribution during liver injury. Carbon tetrachloride (CCl) was used to establish a liver injury mouse model. PGE was measured by LC-MS/MS. The plasma and hepatic PGE levels were significantly increased at 6 to 48 h after CCl treatment. The ratio of plasma levels of 13,14-dihydro-15-ketoPGE (PGEM), a major PGE metabolite, to PGE decreased significantly after CCl treatment. PGE synthesis and expression of enzymes related to PGE production were not induced, while the activity and mRNA expression of 15-prostaglandin dehydrogenase (15-PGDH/Hpgd), a major enzyme for PGE inactivation, decreased significantly in the liver of CCl-treated mice compared to that of vehicle-treated control. The plasma and hepatic PGE levels were negatively correlated with the hepatic mRNA expression levels of Hpgd. Although the mRNA expression of organic anion transporting polypeptide 2A1 (OATP2A1/Slco2a1), a major PGE transporter, was upregulated, other hepatic OATPs decreased significantly at 24 h after CCl treatment. Immunohistochemical analysis indicated that 15-PGDH was mainly expressed in endothelial cells and that OATP2A1 was expressed at least in endothelial cells and Kupffer cells in the liver. These results suggest that the decreased 15-PGDH expression in hepatic endothelial cells is the principal mechanism for the increase in hepatic and plasma PGE levels due to the CCl-induced liver injury.