Maternal bacterial infections impact expression of drug transporters in human placenta.
BACKGROUND
Several efflux and uptake transporters in the placenta are involved in the transmembrane transport of endogenous substrates and xenobiotics. Their expression and function may be altered in maternal complications associated with inflammation. Our objective was to examine the effect of chorioamnionitis, a bacterial intra-amniotic infection on the expression of clinically important transporters in human placenta.


METHODS
Human placental samples were collected from preterm and term pregnancies diagnosed with chorioamnionitis infection and were gestational age-matched with samples from pregnancies with no obstetric complications, using predefined exclusion criteria. Transporter protein expression was quantified using Western blots while cytokine and transporter mRNA expression was measured via real-time polymerase chain reaction.


RESULTS
mRNA levels of pro-inflammatory cytokines IL-6, IL-1β and TNF-α were markedly elevated by 2.5- to 3-fold in preterm placentas with infection, relative to preterm controls (p<0.05). Expression of ABCG2 and SLCO2B1 was downregulated by 48 to 57% (p<0.05) in placentas from women with infection and preterm parturition, relative to preterm healthy controls. Protein and mRNA expression changes were generally consistent. At term, ABCG2 mRNA and SLCO2B1 protein expression levels were significantly downregulated, relative to controls. Significant changes in ABCB1 and SLCO4A1 expression were not observed, however ABCB1 transcript levels strongly correlated with IL-6, IL-1β and TNF-α expression (p<0.001), potentially suggesting involvement of cytokine-mediated regulation.


CONCLUSIONS
Collectively, these data show that maternal infections impact the expression of key drug transporters in placenta, suggesting that materno-fetal drug transport may be altered by changes in placental expression of ABC and OATP transporters.
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
Vanja
V
Petrovic
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
Dea
D
Kojovic
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
Alex
A
Cressman
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada. Electronic address: m.piquette.miller@utoronto.ca.
Micheline
M
Piquette-Miller
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D002821:Chorioamnionitis / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008431:Maternal-Fetal Exchange; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D010599:Pharmacokinetics; D010920:Placenta / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000276:immunology*; D015262:Xenobiotics / Q000378:metabolism*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D016207:Cytokines; D018836:Inflammation Mediators; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; C450859:SLCO2B1 protein, human; D015262:Xenobiotics
Chorioamnionitis; Cytokines; Drug transporters; Infection; Inflammation; Placenta