霉酚酸对丙型肝炎病毒复制的抑制作用

Inhibition of hepatitis C virus replication by mycophenolic acid in hepatocytes

目的调查临床使用的免疫抑制剂，包括霉酚酸、雷帕霉素和他克莫司（FK-506）对肝细胞中HCV复制的影响。方法用各种免疫抑制剂处理HCVJFH-1感染的肝细胞，利用实时定量RTPCR检测HCVRNA的水平，用WesternBlot检测HCV核心蛋白表达水平。结果用霉酚酸处理HCVJFH-1感染的肝细胞，可以极大地降低HCVRNA的水平和减少HCV核心蛋白的表达；雷帕霉素和FK-506对HCV复制的影响不大。外源性鸟嘌呤核苷可以逆转霉酚酸对HCV复制的抑制作用。结论在肝细胞中霉酚酸通过耗尽细胞的鸟嘌呤核苷抑制HCV复制。霉酚酸在临床上可能有益于HCV感染的肝移植患者。

Objective It is well known that cyclosporine A （CsA）, a widely used immunosuppressant for clinical organ transplantation, has the ability to inhibit HCV replication. In this study, the effects of several other immunosuppressants, including mycophenolic acid （MPA）, rapamycin and FK-506, on HCV replication were examined in human hepatocytes. Methods HCV JFH-1-infected hepatocytes were treated with immunosuppressants or with control vehicles. The levels of viral RNA and the expression of HCV core protein were determined by quantitative real-time RT-PCR and Western Blot assay, respectively. Results MPA-treated cells showed significant decreases in both viral RNA and HCV Core protein expression compared with the control cells. Moreover, MPA treatments of hepatocytes before, during or after HCV infection could significantly inhibit viral replication. In contrast, rapamycin and FK-506 had little effect on I-ICV replication. Mechanism research disclosed that the inhibition of HCV replication by MPA was mainly due to its depletion of guanosine, a purine nucleoside crucial for synthesis of guanosine triphosphate （ GTP）, which is required for initiation of HCV RNA replication. The supplement of exogenous guanosine could reverse most of anti-HCV effect of MPA. Conclusion These results indicate that MPA, through the depletion of guanosine, inhibits HCV JFH-1 replication in hepatocytes, suggesting that MPA may be beneficial for HCV-infected transplant recipients.