Modulation of Placental Breast Cancer Resistance Protein by HDAC1 in Mice: Implications for Optimization of Pharmacotherapy During Pregnancy

Abstract

Breast cancer resistance protein (BCRP/ABCG2) is a critical drug efflux transporters by limiting drugs’ transplacental transfer rates. More investigations on the regulation of placental BCRP offer great promise for enabling pronounced progress in individualized and safe pharmacotherapy during pregnancy. Histone deacetylases (HDACs) play an important role in epigenetic regulation of placental genes. It was reported recently by us that HDAC1 was involved in placental BCRP regulation in vitro. The aim of this study was to further explore the effect of HDAC1 on placental BCRP expression and functionality in animals. Randomly assigned C57BL pregnant dams received intraperitoneal injections of a negative control siRNA or Hdac1 siRNA from embryonic day 7.5 (E7.5) to E15.5, respectively. At E16.5, glyburide (GLB), a probe for evaluating placental BCRP efflux functionality, was injected via the tail vein. Animals were sacrificed through cervical dislocation at various times (5–180 min) after drug administration. The maternal blood, placentas, and fetal-units were collected. GLB concentrations were determined by a validated high-performance liquid chromatography/mass spectrometry (HPLC-MS) assay. Real-time quantitative PCR (qRT-PCR), Western blot, and immunohistochemical (IHC) analysis were employed to identify mRNA/protein levels and localization of gene expressions, respectively. It was noted that Hdac1 inhibition significantly decreased placental Bcrp expression, with markedly increases of GLB concentrations and area under the concentration-time curve (AUC) in fetal-units. Particularly, the ratios of fetal-unit/maternal plasma GLB concentrations were also significantly elevated following Hdac1 repression. Taken together, these findings suggested that HDAC1 was involved in positive regulation of placental BCRP expression and functionality in vivo.