(Hypertension. 1997;29:500.)
© 1997 American Heart Association, Inc.
State-of-the-Art-Lecture |
Kidney 11ß-HSD2 Is Inhibited by Glycyrrhetinic Acid-Like Factors in Human Urine
From the Department of Pathology and Laboratory Medicine, The Miriam Hospital, Woman and Infants Hospital (H.S.), and Rhode Island Hospital (A.S.B.), Brown University School of Medicine, Providence, RI.
Correspondence to Dr David J. Morris, Department of Pathology and Laboratory Medicine, The Miriam Hospital/Brown University, 164 Summit Ave, Providence, RI 02906
We have previously shown that human urine contains substances that, like glycyrrhetinic acid, inhibit 11ß-HSD1. We have named these substances "glycyrrhetinic acid-like factors" or GALFs. We now have found that human urine contains measurable quantities of both 11ß(HSD1)- and 11ß(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 11ß(HSD1)- and 11ß(HSD2)-GALFs can be extracted directly from urine into ethyl acetate, yielding fraction EA1. Hydrolysis of the GALFs remaining in the aqueous phase by ß-glucuronidase markedly increases the total amounts of GALFs, with the majority now being ethyl acetate extractable (fraction EA2). These EA2 posthydrolysis 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 11ß-HSD1 and 11ß-HSD2. The others are peaks with specific 11ß(HSD 1)- and 11ß(HSD2)-GALF inhibitory activity. The GALFs in the same posthydrolysis EA2 extract are also inhibitory toward the 11ß-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 11ß-HSD2 is selectively inhibited by 5
-(but not by 5ß-) reduced steroids. GC-MS analysis of the 11ß(HSD2)-GALFs in EA2 is now being performed to determine whether this group includes 3,5-ring A-tetrahydro-reduced derivatives of steroids.
Key Words: licorice • hydroxysteroid dehydrogenase • glycyrrhetinic acid • urine • GALF • pregnancy
Abbreviations: 11ß-HSD = 11ß-hydroxysteroid dehydrogenase • 11-dehydrpo-B = 11-dehydrocorticosterone • AME = apparent mineralocorticoid excess • CBX = carbenoxolone sodium • DOC = deoxycorticosterone • EA = ethyl acetate • GA = glycyrrhetinic acid • GALF = glycyrrhetinic acid-like factor • HPLC = high-performance liquid chromatography • MC = mineralocorticoids • MR = mineralocorticoid receptor • VSM = vascular smooth muscle
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