Apoptotic injury in cultured human hepatocytes induced by HMG-CoA reductase inhibitors
Apoptotic injury in cultured human hepatocytes induced by HMG-CoA reductase inhibitors
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DOI：
10.1016/j.bcp.2004.02.037
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发表时间：
2004-06-15
影响因子：
5.8
通讯作者：
Oishi, R
中科院分区：
文献类型：
--
作者：
Kubota, T;Fujisaki, K;Oishi, R
肝毒性是降脂药物（如他汀类药物）治疗期间的主要主诉，尽管他汀类药物诱导肝损伤的细胞机制尚不完全清楚。使用培养的人肝细胞，我们研究了亲脂性和亲水性他汀类药物对细胞活力的影响。亲脂性他汀类药物（包括辛伐他汀、洛伐他汀、西立伐他汀、氟伐他汀和阿托伐他汀）通过线粒体酶活性降低WST-8而降低肝细胞活力，然而，亲水性普伐他汀不会引起细胞损伤。辛伐他汀诱导的细胞活力丧失被甲羟戊酸或焦磷酸香叶基香叶基酯减弱。辛伐他汀诱导DNA片段化，增加膜联蛋白V和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记染色的细胞数量，这两种情况都可被半胱天冬酶抑制剂如zDEVD-festrin、zLEHD-festrin和zIETD-festrin逆转。与这些数据一致，caspase-3，caspase-9和caspase-8的活性被辛伐他汀升高。辛伐他汀降低bcl-2蛋白含量和mRNA表达，而不影响bax mRNA表达。另一方面，亲脂性和亲水性他汀类药物均显著降低内源性胆固醇的含量。这些结果表明，亲脂性他汀类药物通过激活caspase-9和caspase-8后刺激caspase-3导致人肝细胞凋亡损伤，其中可能涉及3-羟基-3-甲基戊二酰辅酶A还原酶的抑制。(C)2004年爱思唯尔公司All rights reserved.
Hepatotoxicity is the major complaint during therapy with lipid-lowering agents such as statins, although the cellular mechanisms underlying the statin-induced liver injury are not fully understood. Using cultured human hepatocytes, we investigated the effects of lipophilic as well as hydrophilic statins on the cell viability. Lipophilic statins, including simvastatin, lovastatin, cerivastatin, fluvastatin and atorvastatin, reduced the viability of hepatocytes as assessed by the mitochondrial enzyme activity to reduce WST-8, however, a hydrophilic pravastatin did not cause cell injury. The simvastatin-induced loss of cell viability was attenuated by mevalonate or geranylgeranyl pyrophosphate. Simvastatin-induced DNA fragmentation and increased the number of cells stained with annexin V and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, both of which were reversed by caspase inhibitors such as zDEVD-fmk, zLEHD-fmk and zIETD-fmk. Consistent with these data, the activities of caspase-3, caspase-9 and caspase-8 were elevated by simvastatin. Simvastatin reduced the protein content and mRNA expression for bcl-2 without affecting bax mRNA expression. On the other hand, both lipophilic and hydrophilic statins significantly reduced the content of endogenous cholesterol. These findings suggest that lipophilic statins cause an apoptotic injury in human hepatocytes by stimulating caspase-3 subsequent to the activation of caspase-9 and caspase-8, in which the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase may be involved. (C) 2004 Elsevier Inc. All rights reserved.