Pathways of Cortisol Metabolism
The principal metabolites of cortisol are shown in Figure 18.2. The enzymes directly metabolizing cor tisol include the A-ring reductases (5a- and 5P-reductases), 6^-hydroxylase, 20-reductase, and 11^-hydroxysteroid dehydrogenases. In rats and mice, which lack 17-hydroxylase in their adrenal cortex, the principal glucocorticoid is corticosterone, which is subject to analogous metabolism.
11 P-Hydroxysteroid Dehydrogenases (1ip-HSDs)
These enzymes catalyse the interconversion of cortisol (or corticosterone) with its inactive metabolite cortisone (or 11-dehydrocorticosterone) (6). Two isozymes have been cloned (7-10) and their characteristics are shown in Table 18.1.
11P-HSD type 2 is a high affinity (low nM Km for cortisol), NAD-dependent dehydrogenase which rapidly converts cortisol to cortisone. Although expressed in many tissues during fetal life (11-14) including the placenta (10,15,16), in adults it is expressed principally in tissues where aldosterone induces its classical effects on sodium excretion, including distal nephron, sweat glands, salivary glands and colonic mucosa (17,18). There is some expression in other epithelial cells, e.g. in lung (19,20) and endothelium (21,22), and in some reports in stromal tissue in lymph nodes (23).
11P-HSD1 is a lower affinity, NADPH-depend-ent enzyme. Although it converts cortisol to cortisone when removed from its intracellular environment, and for several years it was thought to be responsible for inactivation of cortisol in the kidney (24), in most if not all intact cells and organs this enzyme is a predominant reductase, reactivating inert cortisone into cortisol (4,25-29). This preponderant reductive direction in vivo appears to be more due to the intracellular 'context' of 11P-HSD1 in the inner leaflet of the endoplasmic reticulum than to any structural feature, such as glycosylation (30), although the mechanisms determining directionality of the reaction have not been confirmed as yet. 11P-HSD1 is present in kidneys of rats and some other species, but there is negligible 11^-HSD1 expression in adult human kidney (31). However, the 11P-HSD1 isozyme is widely expressed in other tissues (32), including liver, adipose tissue (4,33), lung (34), skeletal muscle, vascular smooth muscle (35,36), anterior pituitary gland, brain (37-39) and adrenal cortex (40).
5a- and 5^-reductases catalyse the reduction of the 4,5 double bond in the A-ring (Figure 18.2) to generate 5a- or 5^-dihydrocortisol. These dihydro-meta-bolites are then subject to rapid metabolism in the liver by 3a-hydroxysteroid dehydrogenase. The latter reaction is not rate-limiting and the majority of cortisol metabolites are excreted as 5a- or 5^-tet-rahydrocortisols. 5a-tetrahydrocortisol is also known as allo-tetrahydrocortisol. These reactions are not significantly reversible. 5^-reductase is expressed mainly in liver, where it also plays a major role in bile acid metabolism (41). 5a-reductase activity is catalysed by two isozymes from different genes (Table 18.2) (42). 5a-reductase type 1 is expressed in liver, non-genital skin, brain and to a lesser extent in stromal cells of adipose tissue (43). In addition to metabolizing cortisol, it also converts testosterone to the more potent androgen receptor agonist 5a-dihydrotestosterone. 5a-reductase type 2 is expressed in human liver, specific areas of the developing central nervous system (CNS) involved in reproductive behaviour, prostate and genital skin. In the latter tissues it is essential to enhance local androgen receptor activation and development of the
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