Cortisol metabolism and its inhibition by glycyrrhetinic acid in the isolated perfused human placental lobule.
We have previously reported the placental metabolism of prednisolone to prednisone, 20alpha- and beta-dihydroprednisone and 20beta-dihydroprednisolone. In this study, the disposition of cortisol was investigated in vitro in the dual perfused, isolated human placental lobule after the addition of cortisol (1.2 micromol, n = 3 and 12 micromol, n = 4) to the maternal compartment. Analysis of 5 h maternal and fetal perfusate samples by high performance liquid chromatography-electrospray-tandem mass spectrometry (HPLC-ESI-MS/MS) revealed that cortisol was mainly metabolized to cortisone, but a significant production of 20alpha-dihydrocortisone, 20beta-dihydrocortisone, 20alpha-dihydrocortisol and 20beta-dihydrocortisol was also detected. Saturability of metabolism but not transfer was demonstrated. Metabolism was eliminated by co-perfusion with the potent 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzyme inhibitor 18beta-glycyrrhetinic acid (GA). The disposition of GA was analysed using HPLC-atmospheric pressure chemical ionisation-MS/MS (HPLC-APCI-MS/MS). GA was found to transfer from the maternal to the fetal circulations without detectable metabolism during 6 h of perfusion.
Dodds
H M
HM
University of Queensland, Department of Medicine, Princess Alexandra Hospital, Brisbane, Australia. hdodds@gpo.pa.uq.edu.au
Taylor
P J
PJ
Johnson
L P
LP
Mortimer
R H
RH
Pond
S M
SM
Cannell
G R
GR
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000287:Administration, Topical; D000893:Anti-Inflammatory Agents / Q000378:metabolism* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006034:Glycyrrhetinic Acid / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D013058:Mass Spectrometry; D010477:Perfusion; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D006034:Glycyrrhetinic Acid; D006854:Hydrocortisone