Review of the toxicology of tamoxifen.

Tamoxifen was carcinogenic to the liver of male and female rats, inducing hepatocellular carcinomas when administered daily by gavage or fed continuously in the diet. It also acted as a promoting agent in a two-stage model of carcinogenesis in rat liver. In contrast, tamoxifen acted as a protective agent in abrogating estrogen-induced hepatotoxicity and hepatocarcinogenesis in hamsters. Tamoxifen did not induce malignancies in mice when administered according to dosing protocols that are effective in inducing hepatocellular carcinomas in rat liver. In the rat, tamoxifen is metabolized to alpha-hydroxytamoxifen, which is further activated to a product that binds principally to the exocyclic amino group of deoxyguanosine in DNA. The same adduct pattern is formed in mouse hepatocytes treated with tamoxifen or its alpha-hydroxylated derivative, and in human hepatocytes exposed to the latter metabolite. However, available data indicate that human cells have a substantially lower capacity than rodent cells for activation of tamoxifen. Tamoxifen also induces aneuploidy in rat hepatocytes in vivo. This evidence has led some investigators to characterize tamoxifen as a carcinogen that acts through both genotoxic and nongenotoxic mechanisms, with the implication that women treated with the drug may be consequently subjected to elevated risk of cancer, particularly of the endometrium. Critical examination of the evidence, however, indicates that extrapolation of these experimental data to humans is subject to very substantial uncertainty. Available data clearly indicate major differences between women and rats with respect to the activation of tamoxifen and formation of DNA adducts, and bring into question the validity of direct extrapolation of data generated in the single susceptible species, the rat, to women in assessing potential risks attendant to tamoxifen administration.