The glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 has broad substrate specificity: Physiological and toxicological considerations

11β-Hydroxysteroid dehydrogenase-type 2 evolved from an ancestral 17β-Hydroxysteroid dehydrogenase-type 2

“…The ancestral 11 -HSD3A may have metabolized novel oxysterols [7,9,11,17,25] or xenobiotics [21][22][23]25,41], as has been found for 11 -HSD1 [ Figure 1]. That is, one or more of the newly described "alternative" functions of 11 -HSD1 [13] may be related to an ancestral function of 11 -HSD3A.…”

“…11 -HSD1 also metabolizes tobacco-specific N-nitrosamines [21][22][23] [ Figure 1]. Thus, the physiological actions and substrates of 11 -HSD1 are complex [13].…”

“…In addition to regulating the synthesis of glucocorticoids, 11 -HSD1 metabolizes various 7-keto-sterols and 7-keto-steroids [7][8][9][10][11][12][13], including 7-keto-cholesterol [11,[14][15]] and 7-keto-dehydroepiandrosterone (DHEA) [10,[16][17] [ Figure 1]. Over-expression of 11 -HSD1 in fat cells leads to metabolic syndrome [18][19][20].…”

“…Over-expression of 11 -HSD1 in fat cells leads to metabolic syndrome [18][19][20]. 11 -HSD1 also detoxifies xenobiotics by reducing their keto-groups [13,[21][22][23] [ Figure 1]. Thus, the physiological actions of 11 -HSD1 are diverse and complex.…”

11β-Hydroxysteroid Dehydrogenase Type 1 and the Metabolic Syndrome

“…Besides inhibition of 11 -HSD1 reductase activity, increase of 11 -HSD1 dehydrogenase (oxidase) activity, without inhibition of 11 -HSD2, may provide a better therapeutic strategy for T2DM, obesity and MetSyn (Ge et al, 2010). 11 -HSD1 is also inhibited by natural compounds, such as an active ingredient of various Chinese herbs (emodin), derivatives or analogues of the licorice root, coffee extract, flavanone (and the monohydroxylated flavonoid 2′-hydroxyflavanone), endogenous steroids and their metabolites and bile acids (Andrews et al, 2003;Atanasov et al, 2006;Chalbot & Morfin, 2006;Classen-Houben et al, 2009;Diederich et al, 2000;Feng et al, 2010;Gathercole & Stewart, 2010;Hollis & Huber, 2011;Latif et al, 2005;Livingstone & Walker, 2003;Maeda et al, 2010;Monder et al, 1989;Morris et al, 2004;Odermatt & Nashev, 2010;Sandeep et al, 2005;Schweizer et al, 2003;Su et al, 2007;Taylor et al, 2008;van Raalte et al, 2009;Walker et al, 1995a;Wamil & Seckl, 2007). Glycyrrhetinic acid, the active pharmacological ingredient of the licorice root and some of its derivatives, as well as its steroidal synthetic analogue carbenoxolone (hemisuccinate derivative of glycyrrhetinic acid) are inhibitors of both 11 -HSD1 and 11 -HSD2 (the magnitude of the effect being dependent on in vitro versus in vivo environment, dose, administration mode, tissue and specie as well as compound structure) (Abdallah et al, 2005;Andrews et al, 2003;Classen-Houben et al, 2009;Gathercole & Stewart, 2010;Hollis & Huber, 2011;Jellinck et al, 1993;Livingstone & Walker, 2003;Monder et al, 1989;Sandeep et al, 2005;Su et al, 2007;…”