title: Progesterone Metabolites Produced by Cytochrome P450 3A Modulate Uterine Contractility in a Murine Model.
abstract: OBJECTIVE
  We seek to characterize the effect of progesterone metabolites on spontaneous and oxytocin-induced uterine contractility.
  
  
  METHODS
  Spontaneous contractility was studied in mouse uterine horns after treatment with progesterone, 2α-hydroxyprogesterone, 6β-hydroxyprogesterone (6β-OHP), 16α-hydroxyprogesterone (16α-OHP), or 17-hydroxyprogesterone caproate (17-OHPC) at 10(-9) to 10(-6) mol/L. Uterine horns were exposed to progestins (10(-6) mol/L), followed by increasing concentrations of oxytocin (1-100 nmol/L) to study oxytocin-induced contractility. Contraction parameters were compared for each progestin and matched vehicle control using repeated measures 2-way analysis of variance. In vitro metabolism of progesterone by recombinant cytochrome P450 3A (CYP3A) microsomes (3A5, 3A5, and 3A7) identified major metabolites.
  
  
  RESULTS
  Oxytocin-induced contractile frequency was decreased by 16α-OHP (P = .03) and increased by 6β-OHP (P = .05). Progesterone and 17-OHPC decreased oxytocin-induced contractile force (P = .02 and P = .04, respectively) and frequency (P = .02 and P = .03, respectively). Only progesterone decreased spontaneous contractile force (P = .02). Production of 16α-OHP and 6β-OHP metabolites were confirmed in all CYP3A isoforms tested.
  
  
  CONCLUSIONS
  Progesterone metabolites produced by maternal or fetal CYP3A enzymes influence uterine contractility.
authors.affiliation: Department of Obstetrics & Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA avi.s.patil@gmail.com.
authors.forename: Avinash S
authors.initials: AS
authors.lastname: Patil
authors.affiliation: Department of Obstetrics & Gynecology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Geeta K
authors.initials: GK
authors.lastname: Swamy
authors.affiliation: Department of Obstetrics & Gynecology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Murtha
authors.affiliation: Department of Obstetrics & Gynecology, Duke University Medical Center, Durham, NC, USA.
authors.forename: R Phillips
authors.initials: RP
authors.lastname: Heine
authors.affiliation: Department of Obstetrics & Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Obstetrics & Gynecology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Grotegut
mesh_terms: D000077713:17 alpha-Hydroxyprogesterone Caproate; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006900:Hydroxylation; D006908:Hydroxyprogesterones / Q000378:metabolism / Q000494:pharmacology; D007527:Isoenzymes; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000201:enzymology; D010120:Oxytocics / Q000494:pharmacology; D010121:Oxytocin / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D014590:Uterine Contraction / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects* / Q000201:enzymology; D008565:Membrane Proteins
chemical_list: D000077713:17 alpha-Hydroxyprogesterone Caproate; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D006908:Hydroxyprogesterones; D007527:Isoenzymes; D010120:Oxytocics; D010121:Oxytocin; D011374:Progesterone; D011994:Recombinant Proteins; C018975:16-hydroxyprogesterone; C048534:6-hydroxyprogesterone; C000592551:cytochrome P450 3A4, mouse; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins
keywords: 16α-hydroxyprogesterone; 17α-hydroxyprogesteone caproate; 6β-hydroxyprogesterone; preterm labor; progesterone