Altered gene expression and activity of human placental drug-metabolizing cytochrome P450 enzymes across gestation

Most medications administered during pregnancy will enter the fetal circulation through the placenta. The activity of placental drug-metabolizing cytochrome P450 (CYP) enzymes modulates the extent of this transfer. However, many gaps exist in understanding how CYP expression and activity vary across gestation and how placental sex influences these changes. Therefore, we aimed to characterize the expression and activity of placental CYPs throughout gestation stratified by sex. Placentas were collected from participants who provided informed consent and received care at the University of Pennsylvania hospital between 18-23.5 weeks gestational age (GA; Tri2, n=27), 20-36^6/7 weeks GA for preterm delivery (preterm, n=40), or 37 to 41 weeks GA for uncomplicated delivery (term, n=40). The DESeq2 R package was used to perform differential expression analysis of CYP gene expression. CYP2C8 and 2D6 activity was measured in vitro using established mass spectrometry assays and analyzed using Kruskal Wallis-ANOVA. Placental expression of CYP1A2, CYP2C8, CYP3A5, and CYP3A7 decreased towards the end of pregnancy, whereasCYP2C9 and CYP2D6 expression increased toward the end of pregnancy. When considering placental sex, CYP2D6 expression was lower in Tri2 vs term in males (log₂ fold change (logFC)=-1.1123) and females (logFC=-1.3750), whereas CYP2C8 was higher in the same comparisons (male logFC=1.4940, female logFC=1.2659). In females only, CYP2D6 and CYP2C8 activity increased in term vs Tri2 placentae (P=0.0004 and P=0.0281, respectively). Consistent with this, female placental CYP2D6 and CYP2C8 activity was positively associated with gestational age (P=0.0020 and P=0.0009, respectively). Placental activity of two CYPs responsible for metabolizing 25% of drugs increases from Tri2 to term in a sex-specific manner, which may affect fetal exposure to maternally administered medications metabolized by these isoforms.