The potentiation of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity by tamoxifen in female CD1 mice

Abstract

Tamoxifen, an antiestrogen commonly used in breast cancer therapy, potentiated the lethality of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) when coadministered to female CD1 mice, despite the virtual lack of toxicity associated with the administration of tamoxifen alone. The 58-day ip LD50 of TCDD was reduced from 330 to 185 micrograms/kg by sc administration of 1 mg/kg/day tamoxifen. A significant dose-response relationship was observed for the potentiating effect of tamoxifen on TCDD lethality. All mice receiving TCDD developed a centrilobular pattern of hepatocellular degeneration and necrosis with perivascular infiltration of inflammatory cells. Clinical chemistry parameters were indicative of liver disease. Abnormalities in mice receiving tamoxifen plus TCDD were similar to, but more severe than, those in mice receiving TCDD only. Seven days after administration of [14C]TCDD, liver retention of radioactivity was increased 80-100% by coadministration of tamoxifen. This elevated retention was associated with a 50 and 37% decrease in excretion of radioactivity by the urinary and fecal routes, respectively. Our results suggest that the potentiation of TCDD toxicity by tamoxifen is associated with decreased excretion of TCDD, leading to elevated liver retention and enhanced severity of liver pathology.