Morris D J, Latif S A, Hardy M P, Brem A S
Brown University Medical School, Providence, RI 02906, USA.
J Steroid Biochem Mol Biol. 2007 May;104(3-5):161-8. doi: 10.1016/j.jsbmb.2007.03.020. Epub 2007 Mar 23.
Two isoforms of 11beta-HSD exist; 11beta-HSD1 is bi-directional (the reductase usually being predominant) and 11beta-HSD2 functions as a dehydrogenase, conferring kidney mineralocorticoid specificity. We have previously described endogenous substances in human urine, "glycyrrhetinic acid-like factors (GALFs)", which like licorice, inhibit the bi-directional 11beta-HSD1 enzyme as well as the dehydrogenase reaction of 11beta-HSD2. Many of the more potent GALFs are derived from two major families of adrenal steroids, corticosterone and cortisol. For example, 3alpha5alpha-tetrahydro-corticosterone, its derivative, 3alpha5alpha-tetrahydro-11beta-hydroxy-progesterone (produced by 21-deoxygenation of corticosterone in intestinal flora); 3alpha5alpha-tetrahydro-11beta-hydroxy-testosterone (produced by side chain cleavage of cortisol); are potent inhibitors of 11beta-HSD1 and 11beta-HSD2-dehydrogenase, with IC50's in range 0.26-3.0 microM, whereas their 11-keto-3alpha5alpha-tetrahydro-derivatives inhibit 11beta-HSD1 reductase, with IC50's in range 0.7-0.8 microM (their 3alpha5beta-derivatives being completely inactive). Inhibitors of 11beta-HSD2 increase local cortisol levels, permitting it to act as a mineralocorticoid in kidney. Inhibitors of 11beta-HSD1 dehydrogenase/11beta-HSD1 reductase serve to adjust the set point of local deactivation/reactivation of cortisol in vascular and other glucocorticoid target tissues, including adipose, vascular, adrenal tissue, and the eye. These adrenally derived 11-oxygenated C21- and C19 -steroidal substances may serve as 11beta-HSD1- or 11beta-HSD2-GALFs. We conclude that adrenally derived products are likely regulators of local cortisol bioactivity in humans.
11β-羟基类固醇脱氢酶（11β-HSD）有两种同工型；11β-HSD1具有双向性（通常还原酶占主导），而11β-HSD2起脱氢酶的作用，赋予肾脏盐皮质激素特异性。我们之前曾描述过人尿中的内源性物质，即“甘草次酸样因子（GALFs）”，它们与甘草一样，既能抑制双向性的11β-HSD1酶，也能抑制11β-HSD2的脱氢酶反应。许多活性更强的GALFs来源于肾上腺类固醇的两个主要家族，即皮质酮和皮质醇。例如，3α5α-四氢皮质酮及其衍生物3α5α-四氢-11β-羟基孕酮（由肠道菌群中皮质酮的21-脱氧反应产生）；3α5α-四氢-11β-羟基睾酮（由皮质醇的侧链裂解产生），都是11β-HSD1和11β-HSD2脱氢酶的强效抑制剂，半数抑制浓度（IC50）在0.26 - 3.0微摩尔范围内，而它们的11-酮基-3α5α-四氢衍生物抑制11β-HSD1还原酶，IC50在0.7 - 0.8微摩尔范围内（其3α5β-衍生物完全无活性）。11β-HSD2的抑制剂会使局部皮质醇水平升高，使其在肾脏中发挥盐皮质激素的作用。11β-HSD1脱氢酶/11β-HSD1还原酶的抑制剂则用于调节血管及其他糖皮质激素靶组织（包括脂肪组织、血管、肾上腺组织和眼睛）中皮质醇局部失活/再激活的设定点。这些源自肾上腺的11-氧化C21和C19甾体物质可能充当11β-HSD1或11β-HSD2的GALFs。我们得出结论，源自肾上腺的产物可能是人体局部皮质醇生物活性的调节因子。
