The inhibition of tamoxifen on UGT2B gene expression and enzyme activity in rat liver contribute to the estrogen homeostasis dysregulation

Tamoxifen treatment may induce dysregulation of estrogen homeostasis, leading to the occurrence of related adverse reactions. However, the potential mechanisms are still unclear. The

We established links between estrogen metabolism and tamoxifen administration and we proposed that the UGT2B inhibition was involved in the disturbance of estrogen homeostasis and the occurrence of tamoxifen-related adverse reactions.

Compared with the control group, the estrogen homeostasis was disturbed and the expression and activity of UGT2B1 (homology with human UGT2B7) were significantly reduced in the rats administrated with tamoxifen. The inhibitory effect of tamoxifen on UGT2B7 was dominated by hydrophobic and π-π stacking interactions, resulting in a concentration-dependent inhibition of UGT2B7 activity by tamoxifen and the imbalance of ligand-activated transcription factors, leading to abnormal regulation of UGT2B and disturbance of estrogen homeostasis, which in turn led to adverse reactions of tamoxifen.