Expression of CYP450 enzymes in human fetal membranes and its implications in xenobiotic metabolism during pregnancy

Abstract

Background: Environmental exposure to toxicants is a major risk factor for spontaneous preterm birth (PTB, <37 weeks). Toxicants and drugs administered to patients are metabolized primarily by the cytochrome P450 (CYP450) system. Along with the adult and fetal liver, the placenta, a critical feto-maternal interface organ, expresses CYP450 enzymes that metabolize these xenobiotics. However, the contribution of the fetal membranes, another tissue of the feto-maternal interface, to the expression of CYP450 enzymes and the detoxification of xenobiotics remains unknown.

Aims: This study characterized CYP450 expression and determined the functional activity of CYP450 enzymes in fetal membranes.

Main methods: RNA sequencing (RNA-Seq) of placental and fetal membrane tissues and cells was done. Differential expressions of CYP450 genes were compared and validated via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) between the two tissues. The functional activity of major CYP450 enzymes was determined using a fluorophore-based enzymatic assay in the presence and absence of their corresponding inhibitors.

Key findings: With the exception of genes that regulate cholesterol metabolism, the expression profile of CYP450 genes was similar between placental and fetal membranes tissues/cells. RT-qPCR analysis confirmed these findings with significant levels of mRNA for major CYP450 genes being detectable in amnion epithelial cells (AECs) and chorion trophoblasts cells (CTCs). Biochemical analyses revealed significant CYP450 enzymatic activities that were sensitive to specific inhibitors for both AECs and CTCs, suggesting that the genes were expressed as functional enzymes.

Significance: This is the first study to determine global expression of CYP450 enzymes in fetal membranes which may play a role in xenobiotic metabolism during pregnancy. Given that many women are exposed to environmental toxins or require medications during pregnancy, a better understanding of their role in metabolism is required to develop safer therapeutics and prevent adverse outcomes.

Keywords: Cytochrome P450; Drug metabolism; Fetal membrane; Pharmacokinetics; Placenta; Pregnancy; Toxicant metabolism.