Ryu Soo Hyung, Chung Young-Hwa, Lee Jae Kyun, Kim Jeong A, Shin Jung Woo, Jang Myoung Kuk, Park Neung Hwa, Lee Han Chu, Lee Yung Sang, Suh Dong Jin
Department of Internal Medicine, University of Inje College of Medicine, Seoul Paik Hospital, Seoul, Republic of Korea.
Liver Int. 2009 Feb;29(2):308-14. doi: 10.1111/j.1478-3231.2008.01811.x. Epub 2008 Jun 18.
BACKGROUNDS/AIMS: It has been reported that tamoxifen may affect hepatoma cell growth in vitro by suppressing transforming growth factor beta-1 (TGF-beta1) expression, suggesting that tamoxifen might also retard fibrogenesis. Thus, we examined whether tamoxifen might suppress TGF-beta1 expression and consequently inhibit the process of hepatic fibrosis in vivo.
To induce periportal hepatic fibrosis, 50 male adult Sprague-Dawley rats were injected with 0.62 mmol/kg of allyl alcohol, intraperitoneally, twice a week for 8 weeks. Hepatic fibrosis scores, intrahepatic collagen levels and plasma TGF-beta1 expression levels were evaluated in three groups of 10 rats orally administered tamoxifen at 1, 5 and 10 mg/kg, respectively, and in 20 controls. Messenger RNAs (mRNAs) encoding TGF-beta1 and TGF-beta receptors in liver tissue were semiquantified using reverse transcriptase polymerase chain reaction.
Hepatic fibrosis scores decreased progressively as the dose of tamoxifen increased, resulting in a significant change in rats treated with tamoxifen at 10 mg/kg compared with controls (P=0.018). Intrahepatic collagen content was significantly less in the group treated with tamoxifen at 10 mg/kg compared with the control (P=0.045). Plasma TGF-beta1 levels were also significantly lower in rats treated with tamoxifen at 10 mg/kg compared with controls (P=0.007). All three concentrations of tamoxifen tested decreased the expression levels of hepatic TGF-beta1 mRNA and type I TGF-beta receptor (TGF-beta RI) mRNA to similar extents.
Tamoxifen seems to inhibit the process of hepatic fibrosis dose-dependently by suppressing the transcription of TGF-beta1 and TGF-beta RI in an experimental model of periportal hepatic fibrosis.
背景/目的：据报道，他莫昔芬可能通过抑制转化生长因子β1（TGF-β1）的表达来影响体外肝癌细胞的生长，这表明他莫昔芬也可能延缓纤维生成。因此，我们研究了他莫昔芬是否能在体内抑制TGF-β1的表达，从而抑制肝纤维化进程。
为诱导门静脉周围肝纤维化，50只成年雄性Sprague-Dawley大鼠腹腔注射0.62 mmol/kg烯丙醇，每周两次，共8周。分别对三组各10只口服1、5和10 mg/kg他莫昔芬的大鼠以及20只对照组大鼠评估肝纤维化评分、肝内胶原水平和血浆TGF-β1表达水平。使用逆转录聚合酶链反应对肝组织中编码TGF-β1和TGF-β受体的信使核糖核酸（mRNA）进行半定量分析。
随着他莫昔芬剂量增加，肝纤维化评分逐渐降低，与对照组相比，10 mg/kg他莫昔芬治疗组大鼠出现显著变化（P = 0.018）。与对照组相比，10 mg/kg他莫昔芬治疗组的肝内胶原含量显著减少（P = 0.045）。与对照组相比，10 mg/kg他莫昔芬治疗组大鼠的血浆TGF-β1水平也显著降低（P = 0.007）。所测试的三种浓度的他莫昔芬均使肝TGF-β1 mRNA和I型TGF-β受体（TGF-β RI）mRNA的表达水平降低到相似程度。
在门静脉周围肝纤维化的实验模型中，他莫昔芬似乎通过抑制TGF-βI和TGF-β RI的转录来剂量依赖性地抑制肝纤维化进程。
