ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Drug Metabolism and Transport
Estrogen Associations with Human Pregnancy Related Increases in Cytochrome P450 3A Activity
Provisionally accepted
Muluneh M. Fashe1
Jonghwa Lee1Joseph T. Grieco1
John K Fallon1Ian R. Mulrenin1Megan N. Gower1Klarissa D. Jackson1Kim A. Boggess2
Craig R. Lee1*- 1Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- 2School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
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. 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 4𝛽-hydroxycholesterol (4𝛽-OH-CHO) and the 4𝛽-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). Plasma 4𝛽-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 4𝛽-OH-CHO concentrations. Conversely, no association between P4 (r=0.068, p=0.817) or CRT (r=-0.115, p=0.696) concentrations and 4𝛽-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 and total CYP3A protein concentrations in a concentration-dependent manner. 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.
Keywords: Pregnancy, CYP3A4, Hepatic metabolism, Estrone, Estradiol, 4β-hydroxycholesterol
Received: 09 Sep 2025; Accepted: 17 Nov 2025.
Copyright: © 2025 Fashe, Lee, Grieco, Fallon, Mulrenin, Gower, Jackson, Boggess and Lee. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Craig R. Lee, craig_lee@unc.edu
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.