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We have previously shown that human urine contains substances that, like glycyrrhetinic acid, inhibit 11β-HSD1. We have named these substances “glycyrrhetinic acid-like factors” or GALFs. We now have found that human urine contains measurable quantities of both 11β(HSD1)- and 11β(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 11β(HSD1)- and 11β(HSD2)-GALFs can be extracted directly from urine into ethyl acetate, yielding fraction EA1 . Hydrolysis of the GALFs remaining in the aqueous phase by β-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 11β-HSD1 and 11β-HSD2. The others are peaks with specific 11β(HSD 1)- and 11β(HSD2)-GALF inhibitory activity. The GALFs in the same posthydrolysis EA2 extract are also inhibitory toward the 11β-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 11β-HSD2 is selectively inhibited by 5α-(but not by 5β-) reduced steroids. GC-MS analysis of the 11β(HSD2)-GALFs in EA2 is now being performed to determine whether this group includes 3α,5α-ring A-tetrahydro-reduced derivatives of steroids.

Kidney 11β-HSD2 Is Inhibited by Glycyrrhetinic Acid-Like Factors in Human Urine