丙二醇与HS 15对对乙酰氨基酚致肝损伤模型的影响

目的：考察助溶剂丙二醇（PG）与HS 15对对乙酰氨基酚（APAP）肝损伤小鼠模型的影响。方法：采用腹腔注射300 mg·kg^-1的APAP构建肝损伤小鼠模型，通过检测造模后血浆中谷丙转氨酶、谷草转氨酶水平、肝脏组织匀浆中谷胱甘肽含量、肝组织形态学及蛋白免疫印迹结果，分析比较造模前分别采用PG （40%，v/v）与HS 15预处理对APAP致肝损伤模型的影响。采用体外小鼠肝微粒体孵育试验考察PG与HS 15对CYP2E1的抑制作用。结果： PG预处理7 d对APAP致肝损伤模型具有减轻损伤作用，而HS 15对APAP致肝损伤模型的构建无明显影响。蛋白免疫印迹结果表明，与模型组CYP2E1蛋白表达量相比，PG预处理组有显著变化（P<0.01），而HS 15组无明显差别。体外酶孵育实验显示1%（v/v） PG对CYP2E1具有明显的抑制作用（P<0.01）。结论： PG可干扰APAP肝损伤，不适合用作APAP及相关肝保护药物的溶媒，其机制与PG可抑制CYP2E1酶活性有关；HS 15对该模型无明显影响，可用作APAP肝损伤研究的溶媒。

Effects of propylene glycol and HS 15 against acute acetaminophen induced liver injury in mice

OBJECTIVE To investigate the effects of propylene glycol (PG) and HS 15 against acetaminophen induced liver injury in mice.METHODS Acute liver injury was induced by single intraperitoneal injection of acetaminophen (APAP, 300 mg·kg^-1) in C57BL/6 mice. The mice were respectively pretreated with PBS, PG or HS 15 for 7 days prior to the administration of APAP. Plasma levels of alanine aminotransferase and aspartate transaminase, hepatic glutathione levels, liver histological observation together with expression of CYP2E1 were evaluated at designated time points after APAP dosing. Furthermore, inhibition of PG on the activity of mouse CYP2E1 was assessed in vitro with mouse liver microsomes.RESULTS PG pretreatment had significant effects on the liver injury induced by APAP while HS 15 had little effect. Results of Western blot showed that protein expression of CYP2E1 in PG treatment group was different from that in APAP model group (P<0.01). In vitro experiment showed that PG had significant inhibition on CYP2E1 (P<0.01).CONCLUSION PG can attenuate APAP induced liver injury via inhibiting the activity of CYP2E1, which is not appropriate for use as vehicle in APAP related liver injury study. Conversely, HS 15 can be used as solvent in this liver injury model.