CHARACTERIZATION OF THE ESTROGENICITY OF TAMOXIFEN AND RALOXIFENE IN HEPG2 CELLS - REGULATION OF GENE-EXPRESSION FROM AN ERE CONTROLLED REPORTER VECTOR VERSUS REGULATION OF THE ENDOGENOUS SHBG AND PS2 GENES

The estrogenic character of tamoxifen and raloxifene was studied on th ree different genes, an ERE-reporter construct and two endogenous gene s, sex hormone binding globulin (SHBG) and pS2, in two variants of the human liver carcinoma cell line HepG2. On the ERE-reporter construct and the pS2 gene both tamoxifen and raloxifene acted as pure estrogen antagonists, whereas on the SHBG gene they functioned as partial estro gens/antiestrogens at concentrations below 1 mu M and as full ''agonis ts'' at concentrations higher than 1 mu M. The fold stimulatory effect of tamoxifen and raloxifene on SHBG protein expression was similar in the estrogen receptor (ER) expressing HepG2 cells (HepER3) and the pa rental non-ER expressing HepG2 cells at concentrations above 1 mu M. I n contrast, the 17 beta-estradiol analogue moxestrol stimulated SHBG e xpression only in the HepER3 cells. Both tamoxifen and raloxifene had an addictive effect to estrogen receptor-dependent SHBG gene expressio n in the HepER3 cells in the presence of saturating concentrations of moxestrol. However, a significant difference was observed in that a mu ch higher concentration of moxestrol was required to see an additive e ffect of raloxifene compared to tamoxifen. The cytokine IL1-beta compl etely blocked the tamoxifen-dependent induction of SHBG gene expressio n in HepER3 cells, but only partly blocked the effect of moxestrol med iated by the ER. In conclusion, our results suggest that the mechanism for the liver-selective ''estrogenic'' character of tamoxifen and ral oxifene is mediated by a non-ER dependent pathway. (C) 1997 Elsevier S cience Ltd.