The adrenal gland is partitioned into different zones, which contain specific enzymes that produce either glucocorticoids (i.e., cortisol), mineralocorticoids (i.e., aldosterone), or weak adrenal androgens.78,79 Aldosterone is synthesized in the outer region of the adrenal gland (zona glomerulosa). Cortisol is synthesized in the inner regions in the zona fasciculata and reticularis. The same adrenal enzymes share most of the early synthetic steps of these steroids, but they differ markedly in their terminal enzymes. The zona glomerulosa is unique in lacking 17α-hydroxylase, the essential enzyme for cortisol formation. However, the zona glomerulosa is rich in the enzyme aldosterone synthase, which is required for the terminal steps in aldosterone synthesis.78,79 and 80 Aldosterone synthase is a single multifunctional P450 enzyme on the inner mitochondrial membrane that converts corticosterone to aldosterone. It catalyzes three successive hydroxylation steps: (a) conversion of deoxycorticosterone to corticosterone; (b) addition of a hydroxyl group to corticosterone (18-OH-corticosterone); and (c) conversion of 18-OH-corticosterone to an aldehyde, with consequent formation of aldosterone. Two cytochrome P450 enzymes have been found, including 11β-hydroxylase and aldosterone synthase.78 Their genes are located in close proximity (40 kb) on chromosome 8 (8q21-q22) and display 95% homology. In the familial disorder glucocorticoid-remediable hyperaldosteronism, there is hypertension and variable hypokalemia as a result of the formation of a chimeric gene that makes aldosterone synthesis ACTH-dependent78(see Chap. 80).

The mineralocorticoid receptor (steroid receptor type 1 [SR1]) binds both aldosterone and cortisol with equal affinity, whereas the cortisol receptor (steroid receptor type 2 [SR2]) binds only cortisol with high affinity.81,82 Both receptors are part of the steroid/vitamin D/retinoic acid superfamily of transcription regulators. Both receptors have high amino acid homology and may overlap the
actions of progesterone and androgen receptors. In humans, there are two isoforms of the SR1; the α and β isoforms.83,84 The SR1s are found mainly on epithelial cells of the renal tubule, the parotid gland, and the colon. SR1s have been found in vascular smooth muscle, in the heart, and in areas of the brain. These receptors can undergo down-regulation, as seen with sodium loading in which the β isoform expression is decreased.84 In contrast, SR2s are found in most cells of the body.

Glucocorticoids and mineralocorticoids bind to SR1 with equal affinity, and glucocorticoid levels are 1000-fold higher than those of mineralocorticoids; thus, one would expect the receptor to be saturated with cortisol. However, specificity is conferred by the enzyme 11β-hydroxysteroid dehydrogenase (HSD),78,79,85 which oxidizes cortisol to inactive corticosterone, thus allowing aldosterone to bind to its receptor. Thus, coexpression of 11β-HSD and SR1 in tissues appears to be a mechanism by which specificity is conferred to aldosterone action. There are multiple forms of this enzyme in the mammalian kidney,86 including a high density form in the principal and intercalated cells.87 In the syndrome of apparent mineralocorticoid excess, the renal isoform for 11β-HSD₂ is missing, thus allowing the normally high concentrations of cortisol in the kidney to bind to SR1.78 This effect creates an excess Na⁺ reabsorption with resultant hypertension and hypokalemia (see Chap. 80). The active ingredient of licorice, glycyrrhetinic acid, also inhibits 11β-HSD₂ causing an, acquired syndrome of mineralocorticoid excess in humans. However, several questions remain regarding mineral corticoid receptors.87a