11beta-hydroxysteroid dehydrogenase type 2 is the predominant isozyme in the guinea pig placenta: decreases in messenger ribonucleic acid and activity at term

Abstract

The type 2 isozyme of 11beta-hydroxysteroid dehydrogenase (11beta-HSD2) is responsible for inactivating physiologically active glucocorticoids to their inert metabolites. This is the predominant 11beta-HSD isozyme in the human placenta, where it is believed to protect the fetus from high levels of maternal cortisol. Given the similarity in placental structure between the human and the guinea pig (hemomonochorial), we have evaluated the potential of utilizing the guinea pig as a model to study the function and regulation of placental 11beta-HSD2 in fetal development. In this study, we characterized the intrinsic properties of 11beta-HSD in the guinea pig placenta during late pregnancy. The 11beta-HSD activity in the placenta was characteristic of 11beta-HSD2 in that it possessed only dehydrogenase activity that was NAD-dependent and had a high affinity for cortisol (Km = 134 nM). Moreover, the level of the 11beta-HSD2-like activity decreased significantly at term. To verify the expression of 11beta-HSD2 gene and to determine whether corresponding changes in 11beta-HSD2 mRNA occur at term, we also cloned the cDNA encoding guinea pig placental 11beta-HSD2. The deduced guinea pig 11beta-HSD2 enzyme contains 395 amino acids and shares over 80% sequence identity with other mammalian 11beta-HSD2 proteins. Northern blot analyses demonstrated the presence of the mRNA for 11beta-HSD2 but not that for 11beta-HSD1. Moreover, the level of 11beta-HSD2 mRNA decreased significantly at term. The parallel decrease in levels of 11beta-HSD2 activity and mRNA at term is consistent with, and provides a plausible molecular basis for, the previously reported increase in the rate of placental transfer of cortisol between mother and fetus at that time. In conclusion, the present study demonstrates that the guinea pig resembles the human in that 11beta-HSD2 is the predominant, if not exclusive, isozyme expressed in the placenta. Therefore, the guinea pig appears to represent a suitable model in which to study the role of placental 11beta-HSD2 in human fetal development.