Most drugs administered during pregnancy will enter the fetal circulation via the placenta. The extent of this transfer is modulated by the activity of placental drug-metabolizing cytochrome P450 (CYP) enzymes. However, many gaps exist in understanding how CYP expression and activity change across gestation and how placental sex influences these changes. Therefore, this study aimed to characterize the expression and activity profiles of placental CYPs across gestation stratified by sex.
Placentas were collected from participants who gave informed consent and received care at the hospital of the University of Pennsylvania between 18-23.5 weeks gestational age (GA; second trimester), 20 0/7 to 36 6/7 weeks GA for preterm delivery (preterm), or 37 to 41 weeks GA for uncomplicated delivery (term). Differential expression analysis of CYP gene expression was performed using the DESeq2 R package; a log fold change (logFC) of ±1 with a false discovery rate (FDR) <0.05 was considered biologically significant. Activity of CYP2C8 and 2D6 activity was assessed in vitro using established mass spectrometry assays and analysed using KW-ANOVA.
CYP2D6 and CYP2C8 were differentially expressed in the second trimester vs term in males and females (CYP2D6: male logFC=-1.1123, female logFC=-1.3750; CYP2C8: male logFC=1.4940, female logFC=1.2659). CYP2D6 and CYP2C8 activity increased in term vs second-trimester placentas (P=0.0125 and P=0.0119, respectively), irrespective of sex. In females only, CYP2D6 and CYP2C8 activity was positively associated with gestational age (P=0.0085 and P=0.0009, respectively).
These findings highlight that the placental activity of two CYPs responsible for the metabolism of 25% of drugs increases from second trimester to term, which may impact fetal exposure to maternally administered drugs metabolized by these isoforms.