Nuclear receptors in regulation of biotransformation enzymes and drug transporters in the placental barrier

Abstract

Over the past 20 years, the toxicological and protective roles of the placental barrier with respect to drug detoxification and transporter-controlled protection of the fetus have been intensively examined. Several cytochrome P450 enzymes are expressed in placental trophoblast at different stages of pregnancy, though only a few of these have functional activity to metabolize xenobiotics. Drug transporters such as P-glycoprotein/MDR1 or breast cancer resistance protein (BCRP) are highly expressed in the placenta, and their functional activities have been demonstrated in the placenta both in vitro and in vivo. In addition, several studies have reported on ligand-activated transcription factors and nuclear receptors referred to as “xenosensors” in the placenta. The xenosensors control transcriptional regulation of both xenobiotic-metabolizing enzymes and drug transporters in different organs. Their ligands include toxic compounds and environmental pollutants, drugs, as well as herbal, dietary or vitamin supplements. Nevertheless, it remains debatable whether the placental barrier adapts to toxic injuries coming either from maternal medication or environmental contamination and whether the placenta contains a mechanism to respond dynamically in protecting the developing fetus. In the present paper, we summarize current knowledge about the activity and expression of major ligand-activated transcriptional mechanisms involved in biotransformation enzymes and transporters regulation in human placenta. In particular, we highlight the emerging roles of aryl hydrocarbon (AHR), vitamin D (VDR), glucocorticoid (GR) and pregnane X (PXR) receptors in that regulation. We show that the placenta constitute a unique metabolizing organ with significant overlap of exogenous and endogenous compounds metabolism controlled by nuclear receptors.

• Cytochrome P450
• gene regulation
• nuclear receptor
• induction
• placenta
• placenta barrier
• transporters

Acknowledgments

We acknowledge Lucie Stejskalova, Katerina Pospechova, Radim Vrzal, Zdenek Dvorak, Petr Nachtigal, Lenka Vecerova, Laura Mesa Perez, Lukas Cerveny and Martina Ceckova for their assistance in our research of the placental xenobiotic metabolizing enzymes and transporters regulations.