Effect of glucocorticoids on regulation of placental multidrug resistance phosphoglycoprotein (P-gp) in the mouse.
Previously, we and others have shown that placental Abcb1 mRNA and phosphoglycoprotein (P-gp; encoded by Abcb1 mRNA) decreases over the second half of gestation, resulting in increased accumulation of P-gp substrates in the fetal compartment. Very little is known pertaining to the regulation of placental Abcb1 mRNA and P-gp. In non-placental adult murine tissues, synthetic glucocorticoids have been shown to regulate Abcb1 (Abcb1a and Abcb1b) mRNA in an isoform and tissue-specific manner. Furthermore, given that maternal and fetal endogenous glucocorticoid levels increase dramatically in late gestation, we hypothesized that synthetic glucocorticoids down-regulate placental Abcb1 and P-gp expression, consequently decreasing placental P-gp mediated fetal protection. Pregnant FVB mice were treated with dexamethasone (0.1 mg/kg or 1 mg/kg; s.c.) or vehicle (saline) from either embryonic day (E)9.5-15.5 or E12.5-E18.5 and then injected with [3H]digoxin (i.v.) to assess placental P-gp function. Dexamethasone treatment from E12.5-E18.5 significantly up-regulated Abcb1a mRNA (1 mg/kg) and P-gp (0.1 mg/kg and 1 mg/kg) expression on E18.5; however, this did not correlate to changes in drug accumulation in the fetal compartment. Similarly, dexamethasone (1 mg/kg) treatment during mid-gestation (E9.5-E15.5) significantly increased placental Abcb1a mRNA. In conclusion, glucocorticoids exhibit complex regulation of the P-gp transport system at the level of gene transcription and translation. Dexamethasone exposure up-regulates Abcb1a mRNA and P-gp protein, particularly in late gestation. However, these changes do not appear to be reflected by changes in P-gp mediated drug transfer. While the latter is somewhat reassuring with respect to antenatal use of glucocorticoids for management of preterm labour, further studies are required to understand regulation of these important drug transporters in the placenta.
Petropoulos
S
S
Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Gibb
W
W
Matthews
S G
SG
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D004077:Digoxin / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D051379:Mice; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D015854:Up-Regulation
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D005938:Glucocorticoids; D004077:Digoxin; D003907:Dexamethasone; C507084:Abcb1b protein, mouse