Abstract
Endogenous selective inhibitors of 11ß-hydroxysteroid dehydrogenase isoforms 1 and 2 of adrenal origin
Latif,Syed A.; Pardo,Hector A.; Hardy,Matthew P.; Morris,David J.
Molecular and Cellular Endocrinology 243(1-2): 43-50
Publication date: 2005
In earlier studies [Latif, S.A., Sheff, M.F., Ribeiro, C.E., Morris, D.J., 1997. Selective inhibition of sheep kidney 11ß-hydroxysteroid-dehydrogenase isoform 2 activity by 5a-reduced (but not 5ß) derivatives of adrenocorticosteroids. Steroids 62, 230-237], only derivatives of steroid hormones possessing the 5a-Ring A-reduced configuration selectively inhibited 11ß-HSD2-dehydrogenase, whereas their 5ß-derivatives were inactive. This present study focuses on an expanded group of endogenous 11-oxygenated, 5a and 5ß-Ring A-reduced metabolites of adrenocorticosteroids, and progestogen and androgen steroid hormones. These substances were tested for their inhibitory properties against 11ß-HSD2, 11ß-HSD1-dehydrogenase and 11ß-HSD1 reductase.The present studies showed that the following compounds stand out as potent inhibitors. These are 5a-DH-corticosterone, 3a,5a-TH-corticosterone, 11ß-OH-progesterone, 11ß-OH-allopregnanolone, 11ß-OH-testosterone, and 11ß-OH-androstanediol, inhibitors of 11ß-HSD1-dehydrogenase; 3a,5a-TH-11-dehydro-corticosterone, 11-keto-progesterone, 11-keto-allopregnanolone, and 11-keto-3ß,5a-TH-testosterone, inhibitors of 11ß-HSD1 reductase; 3a,5a-TH-aldosterone, 5a-DH-corticosterone, 3a,5a-TH-corticosterone,11-dehydro-corticosterone, 3a,5a-TH-11-dehydro-corticosterone, 11ß-OH-progesterone, 11-keto-progesterone, 11ß-OH-allopregnanolone, 11-keto-allopregnanolone, 11ß-OH-testosterone, and 11-keto-testosterone, inhibitors of 11ß-HSD2. All of these substances have the potential to be derived from adrenally synthesized corticosteroids. Substances with similar structures to those described may help in the design of exogenous agents for the management of a variety of disease states involving 11ß-HSD isoenzymes.
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