Estrogen associations with human pregnancy related increases in cytochrome P450 3A activity
Year: 2025
Type: article
Abstract: Introduction Increased CYP3A-mediated drug clearance during pregnancy can lead to subtherapeutic dosing of CYP3A substrates. Pregnancy-related hormones (PRHs) increase CYP3A4 expression and activity in cultured human hepatocytes. However, the factors in maternal circulation that regulate pregnancy-mediated changes in CYP3A activity remain unclear. Methods This study investigated the association between maternal plasma concentrations of key steroidal PRHs and biomarkers of CYP3A activity in human pregnancy, and the impact of individual PRHs on CYP3A4 expression in primary human hepatocytes. Concentrations of estrone (E1), estradiol (E2), progesterone (P4), and cortisol (CRT), and 4 β -hydroxycholesterol (4 β -OH-CHO) and the 4 β -OH-CHO:CHO ratio (endogenous biomarkers of CYP3A activity), were quantified in human plasma across a spectrum of pregnancy states: healthy nonpregnant controls (n = 4), healthy pregnant volunteers (n = 6), and pregnant patients diagnosed with preeclampsia (n = 8). Results Plasma 4 β -OH-CHO concentrations (median [25%–75%]) were higher in healthy pregnant (141 [115, 165] ng/mL) and preeclampsia patients (129 [90.5, 191] ng/mL) compared to nonpregnant controls (69.8 [45.8, 82.5] ng/mL). In healthy pregnant and preeclampsia patients, plasma E1 ( r = 0.687, p = 0.007 ) and E2 ( r = 0.551, p = 0.041 ) concentrations positively correlated with plasma 4 β -OH-CHO concentrations. Conversely, no association between P4 ( r = 0.068, p = 0.817 ) or CRT ( r = -0.115, p = 0.696 ) concentrations and 4 β -OH-CHO were observed. Cultured human female primary hepatocytes were exogenously exposed in vitro to PRHs and absolute CYP protein concentrations were quantified. Consistent with the human plasma sample associations, E1 and E2 induced CYP3A4 mRNA and total CYP3A protein concentrations in a concentration-dependent manner. Discussion Altogether, these data suggest that increased concentrations of E1 and E2 contribute, at least in part, to increased hepatic CYP3A expression and activity during pregnancy in humans.
Source: Frontiers in Pharmacology
Institution: University of North Carolina at Chapel Hill
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
Funders: National Institutes of Health, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences, National Center for Research Resources, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1017297203, G1364044850, Mechanisms of Altered Hepatic Drug Metabolism and Transport in Pregnancy, G4622355042, G5357638189, Phase II Study of Nicotinamide (vitamin B3-amide) in Early-Onset Preeclampsia, G8455164419, UNC Center for Environmental Health and Susceptibility, The UNC Chapel Hill Superfund Research Program (UNC-SRP)
OpenAlex ID: W4416729340