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Tamoxifen and toremifene inhibit the conversion of delta 8-cholestenol to lathosterol so that serum total and LDL cholesterol levels are lowered by downregulation of cholesterol synthesis. Thus, inhibition of the delta 8-isomerase may be the major hypolipidemic effect of these agents. Reduced risk of coronary artery disease will probably occur also during long-term toremifene treatment, because the drug reduces cholesterol and its synthesis, similarly to tamoxifen.

The object of this article is to review briefly the preclinical and clinical safety of some antiestrogens. Tamoxifen, toremifene, droloxifene, and idoxifene are polyphenylethylene antiestrogens, whereas the pure antiestrogen, ICI 182,780 or faslodex, as well as raloxifene, is of a different structure. Tamoxifen has been shown to be genotoxic in several studies. It induces unscheduled DNA synthesis in rat hepatocytes and micronuclei in MCL-5 a cells in vitro. Tamoxifen also induces aneuploidy in rat liver in vivo and chromosome aberrations and micronuclei in mouse bone marrow. Toremifene has also shown to be genotoxic, but to a far lower extent, by inducing micronuclei in MCL-5 a cells in vitro and by inducing aneuploidy in rat liver in vivo. Tamoxifen has been shown to be hepatocarcinogenic in the rat in at least four independent long-term studies. The initiation of tumors in the rat is the result of metabolic activation by cytochrome P450 isoenzymes to an electrophile(s) that binds irreversibly to DNA. The other antiestrogens have not been shown to be carcinogenic in rodents. In several independent clinical studies, the risk of endometrial cancer has increased among tamoxifen-treated women. After reviewing the available data, the International Agency for Research on Cancer concluded that there was sufficient evidence to show that tamoxifen is a class I human carcinogen. The increased risk for endometrial cancer occurs predominantly among women who are 50 years old or older and who have been treated with tamoxifen. It is not yet clear whether the uterine tumor formation is a result of genetic mechanisms, analogous to those seen in the rat liver or due to the estrogen agonist action of tamoxifen. However, the other antiestrogens with a more or less similar intrinsic estrogenic potential have not been shown to be carcinogenic in humans.

The hepatoproliferative and cytochrome P450 enzyme inducing effects of two antiestrogens, tamoxifen and toremifene, were compared in female Sprague-Dawley rats using immunohistochemical staining methods. Equimolar doses of the antiestrogens (tamoxifen 45 mg/kg and toremifene 48 mg/kg) were given by oral administration to 6-week-old rats for 12 months including a 3-month recovery period. Controls received the vehicle carboxymethylcellulose. Altogether 90 rats were used in the study. Five rats per dose group were killed after 14 days, 5 weeks, 3, 6 and 12 months of treatment as well as after the 3-month recovery period. Hepatocellular carcinoma was found in four out of five rats after 12 months of tamoxifen treatment. After the 3-month recovery period all tamoxifen-treated rats had large liver tumors (diameter up to 3 cm). No tumors were observed in toremifene-treated rats. Liver cell proliferation was measured by the index of proliferating cell nuclear antigen (PCNA) expression. Immunohistochemical staining with the placental form of glutathione S-transferase (GST-P) was used as a marker for preneoplastic foci. Cytochrome P450 induction was measured using specific antibodies to isoenzymes. Tamoxifen increased the incidence of GST-P-positive foci significantly by 3 months of treatment but toremifene did not as compared with the controls. Liver cell proliferation increased significantly only in the liver tumors of tamoxifen-treated rats after 12 months of treatment and during the recovery period. Both antiestrogens induced the isoenzymes CYP2B1/2 and CYP3A1 within 14 days although tamoxifen was a more powerful inducer. Immunohistochemistry of rat liver sections showed a centrilobular localization of these induced enzyme proteins. The expression of CYP2B1/2 and 3A1 could also be observed in foci after 3 and 6 months of administration and in liver adenomas and in some carcinomas after 12 months of administration with tamoxifen. The results show that tamoxifen, but not toremifene, has the potential to induce and promote the development of rat hepatocarcinogenesis in this experimental model.

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