P-glycoprotein expression and localization in the rat uterus throughout gestation and labor

Abstract

Uterine tissues contain the efflux transporter P-glycoprotein (P-gp, encoded by Abcb1a/1b gene), but little is known about how it changes through gestation. Our aim was to investigate the expression profile and cellular localization of P-gp in the pregnant, laboring and post-partum (PP) rat uterus. We propose that during pregnancy the mechanical and hormonal stimuli play a role in regulating myometrial Abcb1a/1b/P-gp. Samples from bilaterally and unilaterally pregnant rats were collected throughout gestation, during labor, and PP (n = 4-6/gestational day). RNA and protein were isolated and subjected to quantitative PCR and immunoblotting; P-gp transcript and protein were localized by in situ hybridization and immunohistochemistry. Expression of Abcb1a/1b gene and membrane P-gp protein in uterine tissue (1) increased throughout gestation, peaked at term (GD19-21) and dropped during labor (GD23L); and (2) was upregulated only in gravid but not in empty horn of unilaterally pregnant rats. (3) The drop of Abcb1a/1b mRNA on GD23 was prevented by artificial maintenance of elevated progesterone (P4) levels in late gestation; (4) injection of the P4 receptor antagonist RU486 on GD19 caused a significant decrease in Abcb1 mRNA levels. (5) In situ hybridization and immunohistochemistry indicated that Abcb1/P-gp is absent from myometrium throughout gestation; (6) was expressed exclusively by uterine microvascular endothelium (at early gestation) and luminal epithelium (at mid and late gestation), but was undetectable during labor. In conclusion, ABC transporter protein P-gp in pregnant uterus is hormonally and mechanically regulated. However, its substrate(s) and precise function in these tissues during pregnancy remains to be determined. Reproduction (2016) 152 195-204

P‐Glycoprotein (P‐gp)/ABCB1 plays a functional role in extravillous trophoblast (EVT) invasion and is decreased in the pre‐eclamptic placenta

“…Western blotting, using a rabbit anti‐P‐gp/ABCB1 antibody previously validated in our laboratory, confirmed reduction in P‐gp protein ( P = 0.0012; Figure B). Treatment with Dsi2 siABCB1 resulted in a concomitant reduction in the number of viable cells (24%) as compared to the NC‐1 control ( P = 0.012; Figure C).…”

Physiologically-based pharmacokinetic modelling of long-acting injectable cabotegravir and rilpivirine in pregnancy

“…On the other hand, CAB is a substrate of Multidrug resistance protein 1 (P-glycoprotein 1) and breast cancer resistance protein (BCRP) in vitro [57]. Though pregnancy has been reported to influence the activity of P-glycoprotein 1 and BCRP in rodents [58,59], data in humans are not available. Regardless, the influence of drug transporter activity on the PK of oral CAB appear to be minimal [57].…”

Teaching an old dog new tricks: reactivated developmental signaling pathways regulate ABCB1 and chemoresistance in cancer

“…These include endothelium of the blood-brain-barrier, proximal tubule of the kidney, intestinal epithelium, and liver hepatocytes. Little is known about ABCB1 expression during gestation; it is presumably under the control of transcription factors belonging to developmental signaling pathways that orchestrate the intricate and highly choreographed process of cell growth and patterning [ 10 , 11 ] .…”