目的 研究阿托伐他汀肝毒性損傷作用及機(jī)制。方法 將24只Wistar han雄鼠分為對(duì)照組和阿托伐他汀低（68.5mg/kg）、高劑量組（205.5 mg/kg），按照10 mL/kg的藥液體積給藥，溶媒對(duì)照組ig等體積5% CMC-Na，連續(xù)ig 28 d。檢測血清中天門冬氨酸氨基轉(zhuǎn)移酶（AST）、丙氨酸氨基轉(zhuǎn)移酶（ALT）、堿性磷酸酶（ALP）、尿素氮（BUN）和血肌酐（CRE）的含量，HE染色觀察肝組織病理。在體外，HepG2細(xì)胞經(jīng)傳代培養(yǎng)后，給予阿托伐他汀干預(yù)24 h，檢測細(xì)胞存活率，丙二醛（MDA）水平、Na⁺-K⁺-ATP酶和Ca²⁺-Mg²⁺-ATP酶活性及線粒體膜電位。結(jié)果 與對(duì)照組比較，阿托伐他汀高劑量組大鼠肝細(xì)胞彌漫性腫脹，核分裂多見，部分肝細(xì)胞極性消失，排列紊亂（P<0.05）。與對(duì)照組比較，阿托伐他汀高劑量組給藥后血清中ALT和AST顯著升高（P<0.05、0.01）。在體外，與對(duì)照組比較，阿托伐他汀125、250、500 μmol/L能明顯抑制細(xì)胞存活率（P<0.05、0.001）。與對(duì)照組比較，阿托伐他汀500 μmol/L HepG2細(xì)胞MDA含量明顯升高（P<0.01）。與對(duì)照組比較，阿托伐他汀125 μmol/L能使Na⁺-K⁺-ATP酶活性增強(qiáng)，500 μmol/L使Na⁺-K⁺-ATP酶活性降低（P<0.001）。與對(duì)照組比較，阿托伐他汀125、250、500 μmol/L均能使能使Ca²⁺-Mg²⁺-ATP酶活性降低（P<0.01，0.001）。與對(duì)照組比較，阿托伐他汀125、250、500 μmol/L均能降低線粒體膜電位（P<0.001）。結(jié)論 阿托伐他汀高劑量可導(dǎo)致肝組織損傷，其毒性作用通過破壞細(xì)胞的線粒體膜電位，抑制Na⁺-K⁺-ATP酶、Ca²⁺-Mg²⁺-ATP酶活性，細(xì)胞膜脂質(zhì)過氧化，從而破壞細(xì)胞內(nèi)微環(huán)境的平衡，導(dǎo)致細(xì)胞凋亡和壞死。

Objective To study the hepatotoxic effects and mechanism of atorvastatin. Methods A total of 24 Wistar han male rats were divided into control group, atorvastatin low dose group (68.5 mg/kg) and atorvastatin high dose group (205.5 mg/kg). The rats were ig administered with atorvastatin according to the volume of 10 mL/kg. The rats in the control group were given 5% CMC-Na with the same volume for 28 d. Serum AST, ALT, ALP, BUN, and CRE were measured 28 days later. Liver histopathology was observed by HE staining. In vitro, HepG2 cells were subcultured and treated with atorvastatin for 24 h. The cell survival rate, MDA levels, Na⁺-K⁺-ATPase and Ca²⁺-Mg²⁺-ATPase activity, and the mitochondrial membrane potential were detected. Results Compared with the control group, diffuse hepatocyte swelling and mitosis were more common in the high dose group of atorvastatin, and some hepatocyte polarity disappeared and arranged disorderly (P<0.05). Compared with the control group, ALT and AST levels in highdose group after administration with atorvastatin were significantly increased (P<0.05, 0.01). In vitro, compared with the control group, the cell viability rate was significantly inhibited by atorvastatin in concentration of 125, 250, 500 μmol/L (P<0.05, 0.001). Compared with the control group, the MDA content of HepG2 cells in the atorvastatin 500 μmol/L group was increased significantly (P<0.01). Compared with the control group, the activity of Na⁺-K⁺-ATPase was significantly increased in the atorvastatin 125 μmol/L group, and decreased in the atorvastatin 500 μmol/L group (P<0.001). Compared with the control group, 125, 250 and 500μmol/L of atorvastatin reduced the activity of Ca²⁺-Mg²⁺-ATPase (P<0.01, 0.001). Compared with the control group, atorvastatin 125, 250 and 500 μmol/L could reduce mitochondrial membrane potential (P<0.001). Conclusion Atorvastatin can lead to liver tissue damage, and its toxic effects may by inhibiting Na⁺-K⁺-ATPase, Ca²⁺-Mg²⁺-ATPase activity and increasing lipid peroxidation of cell membrane, and destroying the mitochondrial membrane potential of cells, thus damaging the balance of intracellular microenvironment and leading to cell apoptosis and necrosis.

國家中藥標(biāo)準(zhǔn)化項(xiàng)目（ZYBZH-C-SD-42）