Characterization of Maternal and Fetal CYP3A-Mediated Progesterone Metabolism.

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Quinney SK, Benjamin T, Zheng X, Patil AS

Characterization of Maternal and Fetal CYP3A-Mediated Progesterone Metabolism.

Fetal Pediatr Pathol. 2017 Oct;36(5):400-411. doi: 10.1080/15513815.2017.1354411. Epub 2017 Sep 26.

PubMed ID

28949811 [ View in PubMed

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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. 6beta-hydroxyprogesterone (6beta-OHP) and 16alpha-hydroxyprogesterone (16alpha-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 6beta-OHP and 16alpha-OHP more than 95%. 6beta-OHP and 16alpha-OHP were both produced by CYP3A4 (2.3 and 1.3 microL/min/pmol, respectively) to a greater extent than by CYP3A5 (0.09 and 0.003 microL/min/pmol) and CYP3A7 (0.004 and 0.003 microL/min/pmol). CONCLUSIONS: Maternal clearance of progesterone by hepatic CYP450's is driven primarily by CYP3A4, with limited contributions from CYP3A5 and CYP3A7.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Progesterone	Cytochrome P450 3A5	Protein	Humans	Unknown	Substrate	Details
Progesterone	Cytochrome P450 3A7	Protein	Humans	Unknown	Substrate Inhibitor	Details