title: Impact of 17-alpha-hydroxyprogesterone caproate on cytochrome P450s in primary cultures of human hepatocytes.
abstract: OBJECTIVE
  The aim of this study was to examine the effects of 17-alpha-hydroxyprogesterone caproate (17OHP-C) on the activity and expression of several common hepatic cytochrome P450 (CYP) enzymes.
  
  
  METHODS
  Primary human hepatocytes were pretreated with vehicle or 17OHP-C (0.1 and 1 μmol/L) for 72 hours, then incubated for 1 hour with a cocktail of CYP substrates. The activity of various CYP enzymes was determined by measuring the formation of the metabolites of specific CYP substrates, using liquid chromatography-tandem mass spectrometry. The messenger RNA expression of various CYP enzymes was determined by real-time polymerase chain reaction.
  
  
  RESULTS
  In primary cultures of human hepatocytes, 17OHP-C minimally altered the activity or messenger RNA levels of CYP1A2, CYP2C9, CYP2D6, and CYP3A. However, 17OHP-C at 1 μmol/L increased CYP2C19 activity by 2.8-fold (P < .01) and CYP2C19 expression by 2.4-fold (P < .001), compared with vehicle-treated cells. A strong positive correlation between activity and expression of CYP2C19 was also observed (r = 0.9, P < .001).
  
  
  CONCLUSIONS
  The activity and expression of hepatic CYP2C19 was significantly increased by 17OHP-C in primary cultures of human hepatocytes. This suggests that exposure to medications that are metabolized by CYP2C19 may be decreased in pregnant patients receiving 17OHP-C. Metabolism of substrates of CYP1A2, CYP2C9, CYP2D6, and CYP3A are not expected to be altered in patients receiving 17OHP-C.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA; Magee Womens Research Institute, Pittsburgh, PA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Ali Mohamed
authors.initials: AM
authors.lastname: Alshabi
authors.affiliation: Department of Obstetrics and Gynecology, Magee Womens Hospital, Pittsburgh, PA; Magee Womens Research Institute, Pittsburgh, PA.
authors.forename: Steve
authors.initials: S
authors.lastname: Caritis
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA; Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA; Magee Womens Research Institute, Pittsburgh, PA; Thomas Starzl Transplantation Institute, Pittsburgh, PA; McGovern Institute for Regenerative Medicine, Pittsburgh, PA.
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
mesh_terms: D000077713:17 alpha-Hydroxyprogesterone Caproate; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006908:Hydroxyprogesterones / Q000494:pharmacology*; D011372:Progestins / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry
chemical_list: D015415:Biomarkers; D006908:Hydroxyprogesterones; D011372:Progestins; D000077713:17 alpha-Hydroxyprogesterone Caproate; D003577:Cytochrome P-450 Enzyme System; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19
keywords: 17-alpha-hydroxyprogesterone caproate; drug-drug interaction; metabolism; primary cultures of human hepatocytes