Placental
ATP binding cassette (
ABC) 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
tumor necrosis factor-alpha (
TNF-alpha) or
interleukin (IL)-1beta decreased
mRNA and
protein expression of apical transporters ABCB1/multidrug resistance gene product 1 (MDR1) and ABCG2/
breast cancer resistance
protein (BCRP)
protein by 40 to 50% (P < 0.05). In contrast,
IL-6 increased
mRNA and
protein expression of the basolateral transporter ABCB4/MDR3 (P < 0.05), whereas ABCC1/
MRP1 expression was unaltered. Pretreatment of trophoblasts with
TNF-alpha 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 to 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 shows that proinflammatory
cytokines, sex
steroids, and
growth factors exert independent effects 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 on placental viability and function.