Received for publication June 13, 2006.
Revised January 14, 2007.
Accepted for publication January 16, 2007.

Independent regulation of apical and basolateral drug transporter expression and function in placental trophoblasts by cytokines, steroids and growth factors

Abstract

Placental ABC (ATP binding cassette) transporters protect placental and fetal tissues by effluxing xenobiotics and endogenous metabolites. We have investigated the effects of cytokines and survival/growth factors, implicated in various placental pathologies, on ABC transporter expression and function in primary placental trophoblast cells. Treatment of primary term trophoblasts in vitro with TNF- or IL-1 decreased mRNA and protein expression of apical transporters ABCB1/MDR1 (multidrug resistance gene product-1) and ABCG2/BCRP (breast cancer resistance protein) protein by 40-50% (P<0.05). In contrast, IL-6 increased mRNA and protein expression of the basolateral transporter ABCB4/MDR3 (P<0.05), while ABCC1/MRP1 expression was unaltered. Pretreatment of trophoblasts with TNF- over 48 h resulted in significantly decreased BCRP efflux activity (increased mitoxantrone accumulation) with minimal changes in MDR1/3 activity. Epidermal growth factor (EGF) and insulin-like growth factor-II, on the other hand, significantly increased BCRP expression at the mRNA and protein level (P<0.05); EGF treatment also increased BCRP functional activity. Estradiol stimulated BCRP, MDR1 and MDR3 mRNA and protein expression by 40-60% and increased MDR1/3 functional activity (P<0.05). Progesterone had modest positive effects on MRP1 mRNA and MDR1 protein expression (P<0.05). In conclusion, this study demonstrates that pro-inflammatory cytokines, sex steroids and growth factors exert independent affects on expression of apical and basolateral placental ABC transporters in primary trophoblast. Such changes could alter placental drug disposition, increase fetal susceptibility to toxic xenobiotics and impact upon placental viability and function.

Key words: ABC transporters, drug transport, fetal toxicology, gene regulation, interleukins, p-glycoprotein, steroids, transporters

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