Department of Medicine and Molecular Science, Hiroshima University, Hiroshima-shi 734-8551, Japan.
J Hepatol. 2011 Jul;55(1):11-8. doi: 10.1016/j.jhep.2010.10.017. Epub 2010 Nov 29.
BACKGROUND & AIMS: ME3738 (22β-methoxyolean-12-ene-3β, 24-diol), a derivative of soyasapogenol B, attenuates liver disease in several animal models of acute and chronic liver injury. ME3738 is thought to inhibit replication of hepatitis C virus (HCV) by enhancing interferon (IFN)-β production, as determined using the HCV full-length binary expression system. We examined the effect of ME3738 combined with IFN-α on HCV replication using the genotype 1b subgenomic replicon system and an in vivo mouse HCV model.
HCV replicon cells (ORN/3-5B/KE cells and Con1 cells) were incubated with ME3738 and/or IFN-α, and then intracellular IFN-stimulated genes (ISGs) and HCV RNA replication were analyzed by reverse-transcription-real time polymerase chain reaction and luciferase reporter assay. HCV-infected human hepatocyte chimeric mice were also treated with ME3738 and/or IFN-α for 4 weeks. Mouse serum HCV RNA titer, HCV core antigen, and ISGs expression in the liver were measured.
ME3738 induced gene expression of oligoadenylate synthetase 1 and inhibited HCV replication in both HCV replicon cells. The drug enhanced the effect of IFN to significantly increase ISG expression levels, inhibit HCV replication in replicon cells, and reduce mouse serum HCV RNA and core antigen levels in mouse livers. The combination treatment was not hepatotoxic as evident histologically and did not reduce human serum albumin in mice.
ME3738 inhibited HCV replication, enhancing the effect of IFN-α to increase ISG expression both in vitro and in vivo, suggesting that the combination of ME3738 and IFN might be useful therapeutically for patients with chronic hepatitis C.
ME3738（22β-甲氧基齐墩果酸-12-烯-3β,24-二醇）是大豆皂角苷元 B 的衍生物，可减轻几种急性和慢性肝损伤动物模型的肝病。ME3738 被认为通过增强干扰素（IFN）-β的产生来抑制丙型肝炎病毒（HCV）的复制，这是通过使用 HCV 全长双表达系统确定的。我们使用基因型 1b 亚基因组复制子系统和体内小鼠 HCV 模型研究了 ME3738 与 IFN-α联合对 HCV 复制的影响。
将 HCV 复制子细胞（ORN/3-5B/KE 细胞和 Con1 细胞）与 ME3738 和/或 IFN-α孵育，然后通过逆转录实时聚合酶链反应和荧光素酶报告基因测定分析细胞内干扰素刺激基因（ISGs）和 HCV RNA 复制。还对 HCV 感染的人肝细胞嵌合小鼠进行了 ME3738 和/或 IFN-α治疗 4 周。测量小鼠血清 HCV RNA 滴度、肝内 HCV 核心抗原和 ISG 表达。
ME3738 诱导寡聚腺苷酸合成酶 1 的基因表达并抑制两种 HCV 复制子细胞中的 HCV 复制。该药物增强了 IFN 的作用，显著增加 ISG 表达水平，抑制复制子细胞中的 HCV 复制，并降低小鼠血清 HCV RNA 和核心抗原水平在小鼠肝脏中。联合治疗在组织学上没有显示出肝毒性，也没有降低小鼠血清中的人血清白蛋白。
ME3738 抑制 HCV 复制，增强 IFN-α的作用，增加 ISG 在体外和体内的表达，表明 ME3738 和 IFN 的联合治疗可能对慢性丙型肝炎患者具有治疗作用。
