Francavilla A, Polimeno L, DiLeo A, Barone M, Ove P, Coetzee M, Eagon P, Makowka L, Ambrosino G, Mazzaferro V
Department of Gastroenterology, University of Bari, Italy.
Hepatology. 1989 Apr;9(4):614-20. doi: 10.1002/hep.1840090417.
We have previously shown that changes in estrogen-hepatocyte interaction occur during liver regeneration. Following 70% hepatectomy, estrogen levels in the blood were elevated, the number of estrogen receptors in the liver was increased and there was an active translocation of estrogen receptors from the cytosol to the nucleus. The injection of tamoxifen, an estrogen antagonist, inhibits hepatocyte proliferation following partial hepatectomy. The administration of 1 microgram tamoxifen per gm body weight at zero time or 6 hr after the operation resulted in a significant inhibition both of DNA synthesis and of the number of cells in mitosis. Injections of tamoxifen 12 hr or later after the operation had no effect. Concomitant injections of equimolar amounts of estrogen abolished the inhibition by tamoxifen. The effects of estrogen and tamoxifen were also tested on hepatocytes in primary culture. Estrogens in the presence of 5% normal rat serum stimulated hepatocyte DNA synthesis as determined by [3H]thymidine incorporation and the labeling index, whereas epidermal growth factor-induced DNA synthesis in the absence of normal rat serum was strongly inhibited. Tamoxifen, in contrast, inhibited DNA synthesis of hepatocytes in the presence of 5% normal rat serum and reversed the stimulatory effect of estrogen in the same system. Attempts to elucidate the mechanism of tamoxifen inhibition in vitro indicated that one effect of tamoxifen is to prevent the amiloride-sensitive Na+ influx necessary to initiate hepatocyte proliferation.
我们之前已经表明，雌激素与肝细胞的相互作用在肝脏再生过程中会发生变化。在进行70%肝切除术后，血液中的雌激素水平升高，肝脏中雌激素受体的数量增加，并且雌激素受体存在从细胞质到细胞核的活跃转运。注射雌激素拮抗剂他莫昔芬会抑制部分肝切除术后的肝细胞增殖。在手术零时或术后6小时每克体重注射1微克他莫昔芬，会显著抑制DNA合成以及有丝分裂中的细胞数量。在术后12小时或更晚注射他莫昔芬则没有效果。同时注射等摩尔量的雌激素可消除他莫昔芬的抑制作用。还在原代培养的肝细胞上测试了雌激素和他莫昔芬的作用。通过[3H]胸腺嘧啶核苷掺入和标记指数测定，在5%正常大鼠血清存在的情况下，雌激素刺激肝细胞DNA合成，而在没有正常大鼠血清的情况下，表皮生长因子诱导的DNA合成受到强烈抑制。相比之下，他莫昔芬在5%正常大鼠血清存在的情况下抑制肝细胞的DNA合成，并逆转了同一系统中雌激素的刺激作用。试图阐明他莫昔芬在体外抑制机制的研究表明，他莫昔芬的一个作用是阻止启动肝细胞增殖所需的对氨氯地平敏感的Na+内流。
