The effect of estrogen and tamoxifen on hepatocyte proliferation in Vivo and in Vitro

Abstract

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.

Regressive liver adenomatosis following androgenic progestin therapy withdrawal: a case report with a 10-year follow-up and a molecular analysis

“…Although not initially recognised, there is also an association between oral contraceptive use and LA. It is admitted that tumour development is related to the ethinyl oestradiol component in a dose-dependent manner (15,16). However, the majority of oral contraceptives associate ethinyl estradiol and an androgenic progestin (e.g.…”

Functional modification of CD11c+ liver dendritic cells during liver regeneration after partial hepatectomy in mice†

“…[11][12][13] Recent evidence indicates DC express estrogen receptors (ER) 21 and estrogens can inhibit DC function and promote their tolerogenicity. 21 ER expression was evaluated by flow cytometric analysis and RT-PCR in freshly isolated LDC and SDC, 6 hours after 75% PH or sham operation (control) in Flt3L-pretreated mice.…”

“…Partial hepatectomy in male animals is followed by an almost complete disappearance of serum androgens and their related tissue receptors in a process known as "feminization" of the male regenerating liver. [11][12][13][14] Inhibition of NK cell activity involves only NK cells within the liver, leaving NK isolated from blood or spleen unaffected. This local protective effect against NK cell activity, which appears to be elicited by changes in the level of MHC class I antigen expression after PH, may be necessary for restoration of the original liver mass.…”

O estresse oxidativo na regeneração hepática em ratos

“…Optou-se por animais jovens visto que a idade pode comprometer a resposta regenerativa pós-hepatectomia parcial 20 e a escolha foi por sexo masculino visando atenuar a reconhecida influência dos estrógenos na regeneração hepá-tica 21 . O período de quatorze dias entre a hepatectomia parcial e o sacrifício dos últimos animais (tempo T3) foi estabelecido com base nas evidências experimentais que a regeneração hepática pós-HP nos ratos se completa em, no máximo, duas semanas, podendo inclusive ocorrer muito antes 2,18 .…”