Corticosterone transfer and metabolism in the dually perfused rat placenta: effect of 11beta-hydroxysteroid dehydrogenase type 2.
Although rat is the most widely used model of glucocorticoid programming of the fetus, the role of rat placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in the transplacental pharmacokinetics of the naturally occurring glucocorticoid, corticosterone, has not yet been fully elucidated. In this study, expression of 11beta-HSD2 in the rat placenta on two different gestation days (16 and 22) was examined using quantitative RT-PCR and Western blotting, and dually perfused rat term placenta was employed to evaluate its functional capacity to transfer and metabolize corticosterone. Marked decrease in placental expression of 11beta-HSD2 toward term was observed on both mRNA and protein levels. In perfusion studies, increasing maternal corticosterone concentration from 3 to 200 nM resulted in the fall of 11beta-HSD2 conversion capacity from 64.3 to 16.3%, respectively. Enzyme saturation occurred at about 50 nM substrate concentration. When delivering corticosterone (3 or 100 nM) from the fetal side, a similar decline of 11beta-HSD2 conversion capacity was observed (66.5% and 48.5%, respectively). Addition of carbenoxolone (10 or 100 microM), a non-specific 11beta-HSD inhibitor, to maternal perfusate decreased conversion capacity from 66.7 to 12.6 or 8.1%, respectively. Similarly potent inhibitory effect was observed in feto-maternal studies. Neither saturation nor inhibition of 11beta-HSD2 was associated with transformation of corticosterone in metabolites other than 11-dehydrocorticosterone. These data suggest that 11beta-HSD2 is the principal enzyme controlling transplacental passage of corticosterone in rats and is able to eliminate corticosterone in both maternal and fetal circulations.
Staud
F
F
Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, Hradec Králové CZ-500 05, Czech Republic. staud@faf.cuni.cz
Mazancová
K
K
Miksík
I
I
Pávek
P
P
Fendrich
Z
Z
Pácha
J
J
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002229:Carbenoxolone / Q000494:pharmacology; D003345:Corticosterone / Q000378:metabolism*; D005260:Female; D066298:In Vitro Techniques; D010477:Perfusion; D010920:Placenta / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D011247:Pregnancy / Q000378:metabolism*; D051381:Rats
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D002229:Carbenoxolone; D003345:Corticosterone