Gestational and pregnane X receptor-mediated regulation of placental ATP-binding cassette drug transporters in mice.
The ATP-binding cassette (ABC) drug transporters in the placenta are involved in controlling the exchange of endogenous and exogenous moieties. Pregnane X receptor (PXR) is a nuclear receptor that regulates the hepatic expression of several key ABC transporters, but it is unclear whether PXR is involved in the regulation of these transporters in the placenta. This study explores the role of PXR in the regulation of placental drug transporters. The placental mRNA expression of Mdr1a, Bcrp, and Mrp1, 2, and 3 was examined in PXR knockout (-/-), heterozygote (+/-), and wild-type (+/+) mice by quantitative PCR. The impact of PXR activation was examined in pregnant pregnane-16α-carbonitrile (PCN)-treated mice. Compared with that in controls, the basal expression of Mdr1a, Bcrp, Mrp1, and Mrp2 was significantly higher in (+/-) and (-/-) mice. Alterations in the expression of mdr1a, bcrp, and mrp1, 2, and 3 between gestational day (GD) 10 and GD 17 was dissimilar between (+/+) and (-/-) mice. Although PCN treatment induced maternal and fetal hepatic expression of Cyp3a11; placental expression of transporters were not significantly changed. Overall, our results suggest a repressive role of PXR in the basal expression of several placental transporters and a tissue-specific induction of these target genes after PXR activation.
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Sarabjit S
SS
Gahir
Micheline
M
Piquette-Miller
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism*; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011257:Pregnancy Proteins; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile; D020033:Protein Isoforms; D012333:RNA, Messenger; D011987:Receptors, Steroid; C501412:Abcg2 protein, mouse; C095122:multidrug resistance protein 3