Interactions between dehydroepiandrosterone and glucocorticoid metabolism in pig kidney: nuclear and microsomal 11beta-hydroxysteroid dehydrogenases.
The 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) activates glucocorticoids (GC) by reversibly converting 11-keto-GC to 11-hydroxy-GC, while 11betaHSD2 and 11betaHSD3 only catalyzes the reverse reaction. Recently, rat and human 11betaHSDs were shown to interconvert 7alpha- and 7beta-hydroxy-dehydroepiandrosterone (7alpha- or 7beta-OH-DHEA) with 7-oxo-DHEA. We report that pig kidney microsomes (PKMc) and nuclei (PKN) oxidize 7alpha-OH-DHEA to 7-oxo-DHEA at higher rates with NAD+, than with NADP+. Corticosterone (CS), dehydrocoticosterone (DHC), 11alpha- and 11beta-hydroxyprogesterone, and carbenoxolone completely inhibited these reactions, while 7-oxo-DHEA only inhibited the NAD+-dependent reaction. Conversely, CS oxidation was not inhibited by 7alpha-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 11betaHSD 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.
Robinzon
Boaz
B
Department of Animal Science, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel. robinzon@agri.huji.ac.il
Prough
Russell A
RA
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology* / Q000378:metabolism; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology* / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism; D013552:Swine
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D011725:Pyridines; D009243:NAD; D003687:Dehydroepiandrosterone; D009249:NADP; C117281:3-acetoxyandrost-5-ene-7,17-dione; D042842:11-beta-Hydroxysteroid Dehydrogenases