OII-B-3Effect of maternal inflammation on the expression of ABCB1 and ABCG2 in placenta

Abstract

BACKGROUND The placenta serves as a protective barrier for the fetus. The drug efflux transporters P-glycoprotein (Pgp/ABCB1) and BCRP (ABCG2) are highly expressed in placenta and diminish fetal exposure to xenobiotics. As endotoxin has been shown to suppress the expression of Pgp in many tissues, we examined its effect on Pgp and BCRP expression in placenta, and its impact on the transplacental passage of the Pgp substrate, 99mTc-MIBI. METHODS Pregnant rats were administered endotoxin (LPS, 0.5, 1.0 mg/kg i.p.) or saline (control) on G17. Rats received 99mTc-MIBI (20 MBq i.v.) 20h later, were sacrificed at 24h, and tissues collected. 99mTc-MIBI levels were measured in fetal and placental tissues. Expression of Pgp and BCRP was examined by RT-PCR and Western blots. RESULTS As compared to controls, placental levels of mdr1a/Pgp mRNA were significantly reduced by 57± 3 % and 88± 4 % and BCRP mRNA levels were significantly reduced by 55± 8 % and 99± 0.1 % of control values in rats administered 0.5 or 1.0 mg/kg LPS, respectively. Dose-dependent reductions in the protein expression of Pgp and BCRP were observed. Likewise, 3.5-fold higher levels of 99mTc-MIBI were seen in the fetuses of LPS treated rats (p < 0.05). CONCLUSIONS Endotoxin-induced inflammation imposed significant down-regulation of placental Pgp and BCRP and increased fetal drug accumulation. Hence, maternal diseases can significantly alter the expression and activity of ABC transporters and thereby may contribute to altered fetal drug exposure. Clinical Pharmacology & Therapeutics (2005) 79, P5–P5; doi: 10.1016/j.clpt.2005.12.016