Tamoxifen induces hepatotoxicity and changes to hepatocyte morphology at the early stage of endocrinotherapy in mice

Abstract

Clinically, hepatotoxicity is an inevitable side effect during long-term endocrinotherapy in breast cancer patients. Various studies have reported the specific mechanism and protective methods for this long-term hepatotoxicity, however, the short-term influences of tamoxifen (TAM) on hepatocytes remain to be elucidated. The previous study investigated TAM-induced liver injury at the early stage of endocrine treatment. Mice were assigned into 2 groups: The experiment group was administrated with intraperitoneal (i.p.) injection of 6 mg/kg/day TAM for 2 weeks, and the control group was administrated with i.p. injection of physiological saline of the same dose. Body weights in each group were detected every day, and alanine aminotransferase and aspartate aminotransferase levels were measured every 3 days. Small pieces of the liver tissues were obtained and processed for protein extraction, biochemical detection and histopathological analysis 2 weeks later. The results indicated that TAM decreased the mice body weights. Morphologically, with the treatment of TAM for only 2 weeks, at the microscopic and ultrastructural levels the structure of hepatic cords became blurred in sections of the regions, although the lobules of the liver remained visible. Partially, hepatic cells were swelled in spherical shapes. Nuclei appeared to be pyknotic and exhibited uneven chromatin distribution. In addition, it was observed in the transmission electron microscopy analysis that nuclei became pyknotic and unevenly distributed. The majority of the nuclei were endowed with distinct heterochromatin and thick nucleoli. The mitochondrial cristae became vague and disorganized. Finally, western blotting was used and detected a significant increase of the caspase-3 level in the liver tissues. In conclusion, the experiments elucidated that TAM (6 mg/kg/day) would cause hepatotoxicity at the early stage of endocrine treatment in mice, and the underlying mechanism was involved with hepatocyte apoptosis.