Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan.
Eur J Pharmacol. 2010 Jun 25;636(1-3):145-54. doi: 10.1016/j.ejphar.2010.03.022. Epub 2010 Mar 30.
Lithocholic acid (LCA) feeding causes both liver parenchymal and cholestatic damages in experimental animals. Although pregnenolone-16 alpha-carbonitrile (PCN)-mediated protection against LCA-induced hepatocyte injury may be explained by induction of drug metabolizing enzymes, the protection from the delayed cholestasis remains incompletely understood. Thus, the PCN-mediated protective mechanism has been studied from the point of modification of lipid metabolism. At an early stage of LCA feeding, an imbalance of biliary bile acid and phospholipid excretion was observed. Co-treatment with PCN reversed the increase in serum alanine aminotransferase (ALT) as well as alkaline phosphatase (ALP) activities and hepatic hydrophobic bile acid levels. LCA feeding decreased hepatic mRNA levels of several fatty acid- and phospholipid-related genes before elevation of serum ALT and ALP activities. On the other hand, PCN co-treatment reversed the decrease in the mRNA levels and hepatic levels of phospholipids, triglycerides and free fatty acids. PCN co-treatment also reversed the decrease in biliary phospholipid output in LCA-fed mice. Treatment with PCN alone increased hepatic phospholipid, triglyceride and free fatty acid concentrations. Hepatic fatty acid and phosphatidylcholine synthetic activities increased in mice treated with PCN alone or PCN and LCA, compared to control mice, whereas these activities decreased in LCA-fed mice. These results suggest the possibility that PCN-mediated stimulation of lipogenesis contributes to the protection from lithocholic acid-induced hepatotoxicity.
胆酸（LCA）喂养会导致实验动物的肝实质和胆汁淤积性损伤。虽然孕烯醇酮-16α-腈（PCN）介导的对 LCA 诱导的肝细胞损伤的保护作用可能是通过诱导药物代谢酶来解释的，但对延迟性胆汁淤积的保护作用仍不完全清楚。因此，已经从脂质代谢修饰的角度研究了 PCN 介导的保护机制。在 LCA 喂养的早期阶段，观察到胆汁酸和磷脂排泄的不平衡。与 PCN 共同治疗可逆转血清丙氨酸氨基转移酶（ALT）和碱性磷酸酶（ALP）活性以及肝疏水性胆汁酸水平的升高。LCA 喂养降低了血清 ALT 和 ALP 活性升高前几种脂肪酸和磷脂相关基因的肝 mRNA 水平。另一方面，PCN 共同治疗逆转了磷脂、甘油三酯和游离脂肪酸的肝 mRNA 水平和肝水平的降低。PCN 共同治疗还逆转了 LCA 喂养小鼠胆汁中磷脂的输出减少。单独用 PCN 治疗可增加肝磷脂、甘油三酯和游离脂肪酸的浓度。与对照小鼠相比，单独用 PCN 或 PCN 和 LCA 治疗的小鼠肝脂肪酸和磷酸胆碱合成活性增加，而 LCA 喂养的小鼠则减少。这些结果表明，PCN 介导的脂肪生成刺激可能有助于保护免受胆酸诱导的肝毒性。
