Characterization of Maternal and Fetal CYP3A-Mediated Progesterone Metabolism

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

Research output: Contribution to journalArticle

3 Scopus citations

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 V max. 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)400-411
Number of pages12
JournalFetal and Pediatric Pathology
Volume36
Issue number5
DOIs
StatePublished - Sep 3 2017

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Keywords

  • Progesterone
  • cytochrome P450
  • fetal
  • metabolism
  • pharmacokinetics

ASJC Scopus subject areas

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

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