Kidney 11 beta-HSD2 is inhibited by glycyrrhetinic acid-like factors in human urine.
We have previously shown that human urine contains substances that, like glycyrrhetinic acid, inhibit 11 beta-HSD1. We have named these substances "glycyrrhetinic acid-like factors" or GALFs. We now have found that human urine contains measurable quantities of both 11 beta(HSD1)- and 11 beta(HSD2)-GALF inhibitory substances. Both are markedly elevated in pregnancy. Their chemical and high-performance liquid chromatography (HPLC) characteristics suggest that several of the GALFs are steroidal. Large quantities of neutral 11 beta(HSD1)- and 11 beta(HSD2)-GALFs can be extracted directly from urine into ethyl acetate, yielding fraction EA1. Hydrolysis of the GALFs remaining in the aqueous phase by beta-glucuronidase markedly increases the total amounts of GALFs, with the majority now being ethyl acetate extractable (fraction EA2). These EA2 post-hydrolysis GALFs can be separated by HPLC resulting in at least six components with inhibitory activity against each isoenzyme. Only two GALF peaks are active against both 11 beta-HSD1 and 11 beta-HSD2. The others are peaks with specific 11 beta(HSD1)- and 11 beta(HSD2)-GALF inhibitory activity. The GALFs in the same posthydrolysis EA2 extract are also inhibitory toward the 11 beta-HSD1 that is present in vascular smooth muscle where they may play a role in the mechanisms controlling blood pressure. We have also found that 11 beta-HSD2 is selectively inhibited by 5 alpha- (but not by 5 beta-) reduced steroids. GC-MS analysis of the 11 beta(HSD2)-GALFs in EA2 is now being performed to determine whether this group includes 3 alpha,5 alpha-ring A-tetrahydro-reduced derivatives of steroids.
Lo
Y H
YH
Department of Pathology and Laboratory Medicine, Miriam Hospital, Providence, RI 02906, USA.
Sheff
M F
MF
Latif
S A
SA
Ribeiro
C
C
Silver
H
H
Brem
A S
AS
Morris
D J
DJ
D042842:11-beta-Hydroxysteroid Dehydrogenases; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000494:pharmacology* / Q000652:urine; D006801:Humans; D006868:Hydrolysis; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007668:Kidney / Q000201:enzymology*; D011247:Pregnancy
D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D005966:Glucuronidase; D006034:Glycyrrhetinic Acid