Expression of the breast cancer resistance protein (Bcrp1/Abcg2) in tissues from pregnant mice: effects of pregnancy and correlations with nuclear receptors

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Abstract
The breastcancer resistance protein (BCRP) plays an important role in drug disposition, including limiting drug penetration across the placental barrier. Our goal was to investigate the effects of pregnancy on Bcrp1 expression in pregnant mice. We examined Bcrp1 expression in placenta, kidney, liver, and small intestine at various gestational ages. Bcrp1 protein levels peaked at gestation day ( gd) 15 in placenta, at gd 10 and 15 in kidney, and at gd 15 in liver; however, Bcrp1 protein levels in small intestine did not change significantly with gestational ages. Immunohistochemistry analysis revealed that the cellular localization of Bcrp1 in placenta, kidney, liver, and small intestine was not influenced by pregnancy. Bcrp1 mRNA levels were analyzed by quantitative real-time RT-PCR. In general, the effects of pregnancy on Bcrp1 protein somewhat lagged behind the effects on Bcrp1 mRNA. To further investigate the possible roles of nuclear receptors in the regulation of the Bcrp1 gene during pregnancy, we examined mRNA levels of aryl hydrocarbon receptor (AhR), hypoxia-inducible factor 1α (HIF1α), estrogen receptor α (ERα), estrogen receptor β (ERβ), or progesterone receptor and compared them with those of Bcrp1. Bcrp1 mRNA was significantly correlated with mRNA of AhR, HIF1α, and ERβ in placenta, with mRNA of HIF1α in kidney, and with mRNA of AhR and ERα in liver. These data suggest that Bcrp1 expression in mouse tissues can be altered by pregnancy in a gestational age-dependent manner. Such effects are likely mediated by certain nuclear receptors through a transcriptional mechanism.