Interactions between dehydroepiandrosterone and glucocorticoid metabolism in pig kidney: Nuclear and microsomal 11β-hydroxysteroid dehydrogenases

Abstract

The 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) activates glucocorticoids (GC) by reversibly converting 11-keto-GC to 11-hydroxy-GC, while 11βHSD2 and 11βHSD3 only catalyzes the reverse reaction. Recently, rat and human 11βHSDs were shown to interconvert 7α-and 7β-hydroxy-dehydroepiandrosterone (7α-or 7β-OH-DHEA) with 7-oxo-DHEA. We report that pig kidney microsomes (PKMc) and nuclei (PKN) oxidize 7α-OH-DHEA to 7-oxo-DHEA at higher rates with NAD + , than with NADP + . Corticosterone (CS), dehydrocoticosterone (DHC), 11α-and 11β-hydroxyprogesterone, and carbenoxolone completely inhibited these reactions, while 7-oxo-DHEA only inhibited the NAD + -dependent reaction. Conversely, CS oxidation was not inhibited by 7α-OH-DHEA or 7-oxo-DHEA. PKMc and PKN did not convert 7-oxo-DHEA to 7-OH-DHEA with either NADPH or NADH. Finally, PKN contained a high affinity, NADPH-dependent 11βHSD that reduces DHC to CS. The GC effects on interconversion of DHEA metabolites may have clinical significance, since DHEA and its 7-oxidized derivatives have been proposed for treatment of human autoimmune and inflammatory disorders.

Ovarian localization of 11β-hydroxysteroid dehydrogenase (11βHSD): effects of ACTH stimulation and its relationship with bovine cystic ovarian disease

“…Moreover, because of a decreased content of 11bHSD stimuli accompanied by increased content of 11bHSD inhibitors, the follicular fluid of cysts exerts a net inhibitory effect on 11bHSD2 activity [35], with a decreased inactivation of cortisol in follicular cysts [69]. By contrast, because progesterone is a strong intrafollicular inhibitor of 11bHSD1 activity [70][71][72][73][74][75], ovulation failure and consequent lack of luteinization and low progesterone concentration, characteristic of COD, could exacerbate 11bHSD1 activity and cortisol production.…”

Implication of cortisol and 11β-hydroxysteroid dehydrogenase enzymes in the development of porcine (Sus scrofa domestica) ovarian follicles and cysts

“…Since progesterone and its 11-hydroxy-metabolites are potent inhibitors of cortisol metabolism (Souness et al 1995, Souness & Morris 1996, Sun et al 1998, Thurston et al 2002, Latif et al 2005, Robinzon & Prough 2005, progesterone would be a strong candidate for an intrafollicular inhibitor of 11bHSD1 activity. We had provisionally excluded progesterone as the major 11bHSD1 inhibitor in FF on the basis that progesterone inhibits both 11bHSD1 and 11bHSD2 and elutes from a C18 column at lower methanol concentrations than are required to resolve the predominant 11bHSD1 inhibitor from human and bovine FF (Thurston et al 2002(Thurston et al , 2003a.…”

“…Furthermore, as the inhibitors elute across several methanol concentrations, they might also be various metabolites of steroids or sterols, with varying degrees of hydrophobicity. Recent literature has documented hydrophobic substrates for renal or hepatic 11bHSD1 other than the glucocorticoids, such as DHEA and its metabolites, 7a-and 7b-hydroxy-DHEA (Robinzon et al 2003, Robinzon & Prough 2005, as well as 7b-hydroxy-and 7-ketocholesterol (Hult et al 2004.…”

Cloning, expression and enzyme activity analysis of testicular 11β-hydroxysteroid dehydrogenase during seasonal cycle and after hCG induction in air-breathing catfish Clarias gariepinus

“…However, this was not probed in the present study as we focused on 11ˇ-HSD2 and 11-KT. Another enzyme that should be considered is 11ˇ-HSD3, which was reported to have dehydrogenase activity in pig, chicken and humans using NADP + as cosubstrate [25,27,28]. Furthermore, Baker [29] reported the existence of 11ˇ-HSD3 isoform in medaka, zebrafish and fugu.…”