Impact of polyinosinic/polycytidylic acid on placental and hepatobiliary drug transporters in pregnant rats.
Although inflammation is known to impose changes in the expression and activity of drug transporters, little is known about the impact of inflammatory stimuli on these transporters during pregnancy. Our objective was to study the effect of viral-induced inflammation on key maternal hepatic and placental drug transporters and their endogenous substrates. Acute inflammation was induced in pregnant Sprague-Dawley rats (gestation day 17-18, n = 5-6/group) by single intraperitoneal doses of polyinosinic/polycytidylic acid [poly(I:C)] (2.5 or 5.0 mg/kg) with saline as a control. Tissues were harvested 24 h later. Expression of transporters was measured via real-time polymerase chain reaction and Western blotting. Maternal plasma levels of cytokines, bile acids, and bilirubin and fetal levels of bile acids were examined. Plasma concentrations of interferon-γ, tumor necrosis factor-α, and interleukin-6 were significantly induced in poly(I:C)-treated rats, compared with controls (p < 0.001). Significant down-regulation of placental Abcb1a/b, Abcc1, Abcc3, Abcg2, Slco1a4, and Slco4a1 mRNA and of hepatic Abcc2, Abcg2, Slco1a4, Slc10a1, and Cyp3a2 mRNA was observed in poly(I:C)-treated rats. Hepatic Abcb1b and Abcc3 mRNA levels were significantly induced. Hepatic protein levels of P-glycoprotein, multidrug resistance-associated protein 2, and breast cancer resistance protein were significantly down-regulated relative to those for controls (p < 0.05). Total bile acids in maternal plasma were significantly increased at the higher dose of poly(I:C). In summary, the poly(I:C) model of viral infection imposes significant changes in the expression of key drug transporters in placental and hepatic tissues of pregnant rats. Because many clinically important endogenous and exogenous compounds are substrates of these transporters, inflammation-mediated changes in transporter expression could affect their maternal disposition and fetal exposure.
Petrovic
Vanja
V
Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada.
Piquette-Miller
Micheline
M
D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D001659:Biliary Tract / Q000378:metabolism*; D001663:Bilirubin / Q000097:blood; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005865:Gestational Age; D008099:Liver / Q000378:metabolism*; D008431:Maternal-Fetal Exchange; D026901:Membrane Transport Proteins / Q000096:biosynthesis*; D010920:Placenta / Q000378:metabolism*; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014777:Virus Diseases / Q000276:immunology / Q000378:metabolism
D001647:Bile Acids and Salts; D016207:Cytokines; D026901:Membrane Transport Proteins; D011070:Poly I-C; D001663:Bilirubin