Characterization of Maternal and Fetal CYP3A-Mediated Progesterone Metabolism

Sara Quinney, Tara Benjamin, Xiaomei Zheng, Avinash S. Patil

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Introduction: Progesterone is critical for maintaining pregnancy and onset of labor. We evaluated CYP450-mediated progesterone meta-bolism, specifically the contribution of CYP3A isoforms. Materials and Methods: In vitro progesterone metabolism was characterized in human liver microsomes (HLMs) with and without selective cytochrome P450 inhibitors and in recombinant CYP3A4, CYP3A5, and CYP3A7. 6β-hydroxyprogesterone (6β-OHP) and 16α-hydroxyprogesterone (16α-OHP) metabolites were quantified by HPLC/UV and fit to the Michaelis–Menten equation to determine Km and Vmax. The effect of CYP3A5 expression on progesterone clearance was determined by in vitro in vivo extrapolation. Results: Ketoconazole inhibited formation of both 6β-OHP and 16α-OHP more than 95%. 6β-OHP and 16α-OHP were both produced by CYP3A4 (2.3 and 1.3 µL/min/pmol, respectively) to a greater extent than by CYP3A5 (0.09 and 0.003 µL/min/pmol) and CYP3A7 (0.004 and 0.003 µL/min/pmol). Conclusions: Maternal clearance of progesterone by hepatic CYP450's is driven primarily by CYP3A4, with limited contributions from CYP3A5 and CYP3A7.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalFetal and Pediatric Pathology
DOIs
StateAccepted/In press - Sep 25 2017

Fingerprint

Cytochrome P-450 CYP3A
Progesterone
Mothers
Labor Onset
Ketoconazole
Liver Microsomes
Cytochrome P-450 Enzyme System
Protein Isoforms
High Pressure Liquid Chromatography
Pregnancy
Liver

Keywords

  • cytochrome P450
  • fetal
  • metabolism
  • pharmacokinetics
  • Progesterone

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pathology and Forensic Medicine

Cite this

Characterization of Maternal and Fetal CYP3A-Mediated Progesterone Metabolism. / Quinney, Sara; Benjamin, Tara; Zheng, Xiaomei; Patil, Avinash S.

In: Fetal and Pediatric Pathology, 25.09.2017, p. 1-12.

Research output: Contribution to journalArticle

Quinney, Sara ; Benjamin, Tara ; Zheng, Xiaomei ; Patil, Avinash S. / Characterization of Maternal and Fetal CYP3A-Mediated Progesterone Metabolism. In: Fetal and Pediatric Pathology. 2017 ; pp. 1-12.
@article{2205031bcb1e472a9566bd96a391db9b,
title = "Characterization of Maternal and Fetal CYP3A-Mediated Progesterone Metabolism",
abstract = "Introduction: Progesterone is critical for maintaining pregnancy and onset of labor. We evaluated CYP450-mediated progesterone meta-bolism, specifically the contribution of CYP3A isoforms. Materials and Methods: In vitro progesterone metabolism was characterized in human liver microsomes (HLMs) with and without selective cytochrome P450 inhibitors and in recombinant CYP3A4, CYP3A5, and CYP3A7. 6β-hydroxyprogesterone (6β-OHP) and 16α-hydroxyprogesterone (16α-OHP) metabolites were quantified by HPLC/UV and fit to the Michaelis–Menten equation to determine Km and Vmax. The effect of CYP3A5 expression on progesterone clearance was determined by in vitro in vivo extrapolation. Results: Ketoconazole inhibited formation of both 6β-OHP and 16α-OHP more than 95{\%}. 6β-OHP and 16α-OHP were both produced by CYP3A4 (2.3 and 1.3 µL/min/pmol, respectively) to a greater extent than by CYP3A5 (0.09 and 0.003 µL/min/pmol) and CYP3A7 (0.004 and 0.003 µL/min/pmol). Conclusions: Maternal clearance of progesterone by hepatic CYP450's is driven primarily by CYP3A4, with limited contributions from CYP3A5 and CYP3A7.",
keywords = "cytochrome P450, fetal, metabolism, pharmacokinetics, Progesterone",
author = "Sara Quinney and Tara Benjamin and Xiaomei Zheng and Patil, {Avinash S.}",
year = "2017",
month = "9",
day = "25",
doi = "10.1080/15513815.2017.1354411",
language = "English (US)",
pages = "1--12",
journal = "Fetal and Pediatric Pathology",
issn = "1551-3815",
publisher = "Informa Healthcare",

}

TY - JOUR

T1 - Characterization of Maternal and Fetal CYP3A-Mediated Progesterone Metabolism

AU - Quinney, Sara

AU - Benjamin, Tara

AU - Zheng, Xiaomei

AU - Patil, Avinash S.

PY - 2017/9/25

Y1 - 2017/9/25

N2 - Introduction: Progesterone is critical for maintaining pregnancy and onset of labor. We evaluated CYP450-mediated progesterone meta-bolism, specifically the contribution of CYP3A isoforms. Materials and Methods: In vitro progesterone metabolism was characterized in human liver microsomes (HLMs) with and without selective cytochrome P450 inhibitors and in recombinant CYP3A4, CYP3A5, and CYP3A7. 6β-hydroxyprogesterone (6β-OHP) and 16α-hydroxyprogesterone (16α-OHP) metabolites were quantified by HPLC/UV and fit to the Michaelis–Menten equation to determine Km and Vmax. The effect of CYP3A5 expression on progesterone clearance was determined by in vitro in vivo extrapolation. Results: Ketoconazole inhibited formation of both 6β-OHP and 16α-OHP more than 95%. 6β-OHP and 16α-OHP were both produced by CYP3A4 (2.3 and 1.3 µL/min/pmol, respectively) to a greater extent than by CYP3A5 (0.09 and 0.003 µL/min/pmol) and CYP3A7 (0.004 and 0.003 µL/min/pmol). Conclusions: Maternal clearance of progesterone by hepatic CYP450's is driven primarily by CYP3A4, with limited contributions from CYP3A5 and CYP3A7.

AB - Introduction: Progesterone is critical for maintaining pregnancy and onset of labor. We evaluated CYP450-mediated progesterone meta-bolism, specifically the contribution of CYP3A isoforms. Materials and Methods: In vitro progesterone metabolism was characterized in human liver microsomes (HLMs) with and without selective cytochrome P450 inhibitors and in recombinant CYP3A4, CYP3A5, and CYP3A7. 6β-hydroxyprogesterone (6β-OHP) and 16α-hydroxyprogesterone (16α-OHP) metabolites were quantified by HPLC/UV and fit to the Michaelis–Menten equation to determine Km and Vmax. The effect of CYP3A5 expression on progesterone clearance was determined by in vitro in vivo extrapolation. Results: Ketoconazole inhibited formation of both 6β-OHP and 16α-OHP more than 95%. 6β-OHP and 16α-OHP were both produced by CYP3A4 (2.3 and 1.3 µL/min/pmol, respectively) to a greater extent than by CYP3A5 (0.09 and 0.003 µL/min/pmol) and CYP3A7 (0.004 and 0.003 µL/min/pmol). Conclusions: Maternal clearance of progesterone by hepatic CYP450's is driven primarily by CYP3A4, with limited contributions from CYP3A5 and CYP3A7.

KW - cytochrome P450

KW - fetal

KW - metabolism

KW - pharmacokinetics

KW - Progesterone

UR - http://www.scopus.com/inward/record.url?scp=85029897024&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029897024&partnerID=8YFLogxK

U2 - 10.1080/15513815.2017.1354411

DO - 10.1080/15513815.2017.1354411

M3 - Article

C2 - 28949811

AN - SCOPUS:85029897024

SP - 1

EP - 12

JO - Fetal and Pediatric Pathology

JF - Fetal and Pediatric Pathology

SN - 1551-3815

ER -