Hou Guoqing, Dick Robert, Brewer George J
Department of Human Genetics, University of Michigan Medical School, G061X MBNI, Ann Arbor, MI 48109, USA.
Exp Biol Med (Maywood). 2009 Jun;234(6):662-5. doi: 10.3181/0811-RM-319. Epub 2009 Mar 23.
The background for this study is that we have observed some improvement in cirrhosis in Wilson's disease patients treated with the anticopper medicine, zinc, and another anticopper drug, tetrathiomolybdate, has completely prevented hepatic fibrosis in the carbon tetrachloride mouse model. We hypothesize that in existing cirrhosis, there may be a fine balance between fibrosis formation and fibrosis dissolution, which may be pushed in the direction of dissolution by anticopper drugs. Thus, in this study, we produced hepatic fibrosis in mice by treatment with carbon tetrachloride, then gave half the fibrotic mice tetrathiomolybdate for 3 months, while the other half of the fibrotic mice received nothing for 3 months and served as controls. Tetrathiomolybdate caused a dramatic and significant reduction in fibrosis as measured by hydroxyproline (the major amino acid constituent of collagen) levels, almost back to baseline levels, compared to controls, who had only a slight and nonsignificant reduction. It is clear from this animal study that dissolution of preexisting fibrosis can be strongly catalyzed by lowering copper levels with tetrathiomolybdate. It now becomes important to evaluate whether this approach will work in the human epidemic of cirrhotic disease resulting from diseases such as alcoholism, nonalcoholic steatohepatitis, and hepatitis C.
本研究的背景是，我们观察到用抗铜药物锌治疗的威尔逊病患者的肝硬化有一些改善，并且另一种抗铜药物四硫代钼酸盐在四氯化碳小鼠模型中完全预防了肝纤维化。我们假设，在现有的肝硬化中，纤维化形成与纤维化溶解之间可能存在微妙的平衡，而抗铜药物可能会将这种平衡推向溶解的方向。因此，在本研究中，我们通过用四氯化碳处理使小鼠产生肝纤维化，然后给一半纤维化小鼠服用四硫代钼酸盐3个月，而另一半纤维化小鼠3个月不接受任何处理并作为对照。与仅略有且无显著降低的对照组相比，通过羟脯氨酸（胶原蛋白的主要氨基酸成分）水平测量，四硫代钼酸盐使纤维化显著大幅降低，几乎回到基线水平。从这项动物研究可以清楚地看出，用四硫代钼酸盐降低铜水平可强烈催化已存在的纤维化的溶解。现在评估这种方法在由酒精中毒、非酒精性脂肪性肝炎和丙型肝炎等疾病导致的肝硬化疾病流行中是否有效变得很重要。
