Department of Pharmacy, Faculty of Pharmacy, Kindai University, Osaka, Japan.
Department of Pharmacy, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Japan.
Endocr Regul. 2022 Feb 18;56(1):22-30. doi: 10.2478/enr-2022-0003.
Carbamazepine (CBZ), a widely used antiepileptic drug, is one major cause of the idiosyncratic liver injury along with immune reactions. Conversely, prostaglandin E (PGE2) demonstrates a hepatoprotective effect by regulating immune reactions and promoting liver repair in various types of liver injury. However, the amount of hepatic PGE during CBZ-induced liver injury remains elusive. In this study, we aimed to evaluate the hepatic PGE levels during CBZ-induced liver injury using a mouse model. Mice were orally administered with CBZ at a dose of 400 mg/kg for 4 days, and 800 mg/kg on the 5th day. Plasma alanine transaminase (ALT) level increased in some of mice 24 h after the last CBZ administration. Although median value of hepatic PGE amount in the CBZ-treated mice showed same extent as vehicle-treated control mice, it exhibited significant elevated level in mice with severe liver injury presented by a plasma ALT level >1000 IU/L. According to these results, mice had a plasma ALT level >1000 IU/L were defined as responders and the others as non-responders in this study. Even though, the hepatic PGE levels increased in responders, the hepatic expression and enzyme activity related to PGE production were not upregulated when compared with vehicle-treated control mice. However, the hepatic 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expression and activity decreased significantly in responders when compared with control mice. These results indicate that elevated hepatic PGE levels can be attributed to the downregulation of 15-PGDH expression under CBZ-induced liver injury.
卡马西平 (CBZ) 是一种广泛使用的抗癫痫药物，是导致特发性肝损伤和免疫反应的主要原因之一。相反，前列腺素 E (PGE2) 通过调节免疫反应和促进各种类型肝损伤的肝脏修复，表现出肝保护作用。然而，CBZ 诱导的肝损伤期间肝内 PGE 的量仍不清楚。在本研究中，我们旨在使用小鼠模型评估 CBZ 诱导的肝损伤期间的肝 PGE 水平。 小鼠每天口服给予 CBZ 400mg/kg，连续 4 天，第 5 天给予 800mg/kg。 最后一次给予 CBZ 后 24 小时，部分小鼠的血浆丙氨酸转氨酶 (ALT) 水平升高。虽然 CBZ 治疗组小鼠的肝 PGE 量中位数与载体对照组小鼠相同，但在血浆 ALT 水平>1000IU/L 的严重肝损伤小鼠中，其水平显著升高。 根据这些结果，在本研究中，血浆 ALT 水平>1000IU/L 的小鼠被定义为应答者，其他小鼠为非应答者。即使如此，应答者的肝 PGE 水平升高，但与载体对照组相比，与 PGE 产生相关的肝表达和酶活性并未上调。然而，与对照组相比，应答者的肝 15-羟基前列腺素脱氢酶 (15-PGDH) 表达和活性显著降低。 这些结果表明，在 CBZ 诱导的肝损伤下，15-PGDH 表达下调导致肝 PGE 水平升高。
