Progesterone Metabolites Produced by Cytochrome P450 3A Modulate Uterine Contractility in a Murine Model.
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Patil AS, Swamy GK, Murtha AP, Heine RP, Zheng X, Grotegut CA
Progesterone Metabolites Produced by Cytochrome P450 3A Modulate Uterine Contractility in a Murine Model.
Reprod Sci. 2015 Dec;22(12):1577-86. doi: 10.1177/1933719115589414. Epub 2015 Jun 2.
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- 26037300 [ View in PubMed]
- Abstract
OBJECTIVE: We seek to characterize the effect of progesterone metabolites on spontaneous and oxytocin-induced uterine contractility. STUDY DESIGN: Spontaneous contractility was studied in mouse uterine horns after treatment with progesterone, 2alpha-hydroxyprogesterone, 6beta-hydroxyprogesterone (6beta-OHP), 16alpha-hydroxyprogesterone (16alpha-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 16alpha-OHP (P = .03) and increased by 6beta-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 16alpha-OHP and 6beta-OHP metabolites were confirmed in all CYP3A isoforms tested. CONCLUSION: Progesterone metabolites produced by maternal or fetal CYP3A enzymes influence uterine contractility.
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