Medical Physiology, 3rd Edition

The Adrenal Cortex: Aldosterone

The mineralocorticoid aldosterone is the primary regulator of salt balance and extracellular volume

Aldosterone determines extracellular volume by controlling the extent to which the kidney excretes or reabsorbs the Na+ filtered at the renal glomerulus. Na+ in the extracellular space retains water—it is the primary osmotically active particle in the extracellular space—and thus the amount of Na+ that is present determines the volume of extracellular fluid (see pp. 135–136). The extracellular volume is itself a prime determinant of arterial blood pressure (see pp. 554–555), and therefore aldosterone plays an important role in the maintenance of blood pressure.

The effects of aldosterone on salt balance determine the extracellular volume and should not be confused with the effects of AVP (also known as antidiuretic hormone, or ADH). AVP regulates the free-water balance of the body (see p. 844). Water freely passes across cell membranes and thus affects the concentration of Na+ and other solutes throughout the body (see pp. 135–136). Unlike aldosterone, AVP makes only a small contribution to the maintenance of extracellular volume; instead, AVP regulates serum osmolality and hence the Na+ concentration. Thus, to a first approximation, one can think of aldosterone as the primary regulator of extracellular volume because of its effect on renal Na+ reabsorption, and AVP as the primary regulator of plasma osmolality because of its effect on free-water balance.

The glomerulosa cells of the adrenal cortex synthesize aldosterone from cholesterol via progesterone

As is the case for cortisol, the adrenal cortex synthesizes aldosterone from cholesterol by using P-450 enzymes in a series of five steps. The initial steps in the synthesis of aldosterone from cholesterol follow the same synthetic pathway that cortisol-secreting cells use to generate progesterone (see Fig. 50-2). Because glomerulosa cells are the only ones that contain aldosterone synthase, these cells are the exclusive site of aldosterone synthesis.

1. The cytochrome P-450 SCC enzyme (P-450SCC) produces pregnenolone from cholesterol. This enzyme—or the supply of substrate to it—appears to be the rate-limiting step for the overall process of steroid hormone synthesis.

2. The SER enzyme 3β-HSD, which is not a P-450 enzyme, oxidizes pregnenolone to form progesterone.

3. Because glomerulosa cells have minimal 17α-hydroxylase (P-450c17), they do not convert progesterone to 17α-hydroxyprogesterone. Instead, glomerulosa cells use a 21α-hydroxylase (P-450c21) in the SER to further hydroxylate the progesterone at position 21 and to produce 11-deoxycorticosterone (DOC).

4. In the mitochondria, 11β-hydroxylase (P-450c11) adds an –OH at position 11 to produce corticosterone. This pair of hydroxylations in steps 3 and 4 are catalyzed by the same two enzymes that produce cortisol from 17α-hydroxyprogesterone.

5. The glomerulosa cells—but not the fasciculata and reticularis cells—also have aldosterone synthase (P-450aldo), which first adds an –OH group to the methyl at position 18 and then oxidizes this hydroxyl to an aldehyde group, hence the name aldosterone. This mitochondrial P-450 enzyme, also called 18-methyloxidase, is an isoform of the same 11β-hydroxylase (P-450c11) that catalyzes the DOC-to-corticosterone step. In fact, aldosterone synthase can catalyze all three steps between DOC and aldosterone: 11β-hydroxylation, 18-methyl hydroxylation, and 18-methyl oxidation.

As with cortisol, no storage pool of presynthesized aldosterone is available in the glomerulosa cell for rapid secretion. Thus, secretion of aldosterone by the adrenal is limited by the rate at which the glomerulosa cells can synthesize the hormone. Although ACTH also stimulates the production of aldosterone in the glomerulosa cell, increases in extracellular [K+] and the peptide hormone ANG II are physiologically more important secretagogues. These secretagogues enhance secretion by increasing the activity of enzymes acting at rate-limiting steps in aldosterone synthesis. These enzymes include the SCC enzyme, which is common to all steroid-producing cells, and aldosterone synthase, which is unique to glomerulosa cells and is responsible for formation of the C-18 aldehyde.

Once secreted, ~37% of circulating aldosterone remains free in plasma. The rest weakly binds to CBG (~21%) or albumin (~42%).

Aldosterone stimulates Na+ reabsorption and K+ excretion by the renal tubule

The major action of aldosterone is to stimulate the kidney to reabsorb Na+ and water and enhance K+ secretion. Aldosterone has similar actions on salt and water transport in the colon, salivary glands, and sweat glands. MRs are also present in the myocardium, liver, brain, and other tissues, but the physiological role of mineralocorticoids in these latter tissues is unclear.

Aldosterone, like cortisol and all the other steroid hormones, acts principally by modulating gene transcription (see pp. 90–92). In the kidney, aldosterone binds to both low- and high-affinity receptors. The low-affinity receptor appears to be identical to the GR. The high-affinity receptor is a distinct MR; it has homology to the GR, particularly in the zinc-finger region involved in DNA binding. Surprisingly, MR in the kidney has a similar affinity for aldosterone and cortisol. Because cortisol normally circulates at much higher concentrations than does aldosterone (5 to 20 µg/dL versus 2 to 8 ng/dL), the biological effect of aldosterone on any potential target would be expected to be greatly overshadowed by that of cortisol. (Conversely, aldosterone has essentially no significant glucocorticoid action because aldosterone binds only weakly to its low-affinity receptor—that is, the GR.)

How then do the renal-tubule cells avoid sensing cortisol as a mineralocorticoid? As noted on page 1021, the cells that are targets for aldosterone—particularly in the initial collecting tubule and cortical collecting tubule of the kidney (see p. 766)—contain 11β-HSD2, which converts cortisol to cortisone, a steroid with a very low affinity for MR (see Fig. 35-13C). Unlike 11β-HSD1, which reversibly interconverts cortisone and cortisol, 11β-HSD2 cannot convert cortisone back to cortisol. As a result, locally within the target cell, the cortisol-to-aldosterone ratio is much smaller than the cortisol dominance seen in plasma. In fact, 11β-HSD2 is so effective at removing cortisol from the cytosol of aldosterone target tissues that cortisol behaves as only a weak mineralocorticoid despite the high affinity of cortisol for the so-called MR. Thus, the presence of 11β-HSD2 effectively confers aldosterone specificity on the MR.

In the target cells of the renal tubule, aldosterone increases the activity of several key proteins involved in Na+ transport (see pp. 765–766). It increases transcription of the Na-K pump, thus augmenting distal Na+ reabsorption. Aldosterone also raises the expression of apical Na+ channels and of an Na/K/Cl cotransporter. The net effect of these actions is to increase Na+ reabsorption and K+ secretion. The enhanced K+secretion (see p. 799) appears to occur as a secondary effect to the enhanced Na+ reabsorption. However, the stoichiometry between Na+ reabsorption and K+ secretion in the distal tubule is not fixed.

Aldosterone regulates only that small fraction of renal Na+ reabsorption that occurs in the distal tubule and collecting duct. Although most Na+ reabsorption occurs in the proximal tubule by aldosterone-independent mechanisms, loss of aldosterone-mediated Na+ reabsorption can result in significant electrolyte abnormalities, including life-threatening hyperkalemia and, in the absence of other compensatory mechanisms, hypotension. Conversely, excess aldosterone secretion produces hypokalemia and hypertension (see p. 1030).

In addition to acting via MR, aldosterone also can exert rapid, nongenomic effects by binding to the GPCR known as GPR30 (see p. 989).

Angiotensin II, K+, and ACTH all stimulate aldosterone secretion

Three secretagogues control aldosterone synthesis by the glomerulosa cells of the adrenal cortex. The most important is ANG II, which is a product of the renin-angiotensin cascade. An increase in plasma [K+] is also a powerful stimulus for aldosterone secretion and augments the response to ANG II. Third, just as ACTH promotes cortisol secretion, it also promotes the secretion of aldosterone, although this effect is weak.

Angiotensin II

We introduced the renin-angiotensin-aldosterone axis on pages 841–842. The liver synthesizes and secretes a very large protein called angiotensinogen, which is an α2-globulin (Fig. 50-6). Renin, which is synthesized by the granular (or juxtaglomerular) cells of the juxtaglomerular apparatus (JGA) in the kidney (see p. 727), is the enzyme that cleaves this angiotensinogen to form ANG I, a decapeptide. Finally, angiotensin-converting enzyme (ACE) cleaves ANG I to form the octapeptide ANG II. ACE is present in both the vascular endothelium of the lung (~40%) and elsewhere (~60%). In addition to acting as a potent secretagogue for aldosterone, ANG II exerts powerful vasoconstrictor actions on vascular smooth muscle (see Table 20-8). ANG II has a short half-life (<1 minute) because plasma aminopeptidases further cleave it to the heptapeptide ANG III. imageN50-2

image

FIGURE 50-6 Control of aldosterone secretion. Three pathways (shown in three different colors) stimulate the glomerulosa cells of the adrenal cortex to secrete aldosterone.

N50-2

Metabolism of the Angiotensins

Contributed by Emile Boulpaep, Walter Boron

The liver synthesizes and releases into the blood the α2-globulin angiotensinogen (Agt), which is a plasma glycoprotein that consists of 452 amino acids. Its molecular weight ranges from 52 to 60 kDa, depending on the degree of glycosylation. Angiotensinogen belongs to the serpin (serine protease inhibitor) superfamily of proteins, which also includes antithrombin III (see p. 446 as well as Tables 18-4 and 18-5). The liver contains only small stores of angiotensinogen, which it constitutively secretes. Production by the liver is greatly increased during the acute-phase response (see Box 18-1). Angiotensinogen is synthesized in several tissues other than liver. In addition to the 52- to 60-kDa form of angiotensinogen, a high-molecular-weight (HMW) angiotensinogen complex of 450 to 500 kDa is also present in plasma. Polymorphisms within the angiotensinogen gene may contribute to normal variations in arterial blood pressure and a tendency to develop hypertension.

The juxtaglomerular cells of the kidney—also called granular cells (see p. 727)—are specialized smooth-muscle cells of the afferent arteriole that synthesize and release both the glycoprotein renin (molecular weight 37 to 40 kDa)—pronounced ree-nin—and its inactive precursor prorenin, which is the major circulating form. Prorenin-activating enzymes on endothelial cells convert this prorenin to renin. The kidney is the major source of circulating prorenin/renin, and the liver is responsible for removing renin from the circulation. The half-life of renin in plasma is 10 to 20 minutes. Renin is an aspartyl proteinase that cleaves a leucine-valine bond near the amino (N) terminus of angiotensinogen to release a decapeptide called angiotensin I (ANG I), which is not biologically active. By an alternative pathway, nonrenin proteases can also produce ANG I. The full sequence of ANG I is Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu:

image

Angiotensin-converting enzyme (ACE; molecular weight ~200 kDa) is produced by and attached to endothelial cells. ACE is a dipeptidyl carboxypeptidase (a zinc peptidase) that cleaves ANG I by removing the carboxy-terminal (C-terminal) dipeptide histidine-leucine and producing the octapeptide angiotensin II (ANG II). The ACE cleavage site is a phenylalanine-histidine bond. The sequence of ANG II is Asp-Arg-Val-Tyr-Ile-His-Pro-Phe:

image

ANG II has a half-life in blood of 1 to 3 minutes, indicating that a large fraction is removed in a single pass through the circulation. ANG II acts on G protein–coupled receptors known as AT1 and AT2. In addition, two other receptors are less well characterized: AT3 and AT4. ANG IV (see below) can bind to AT4 receptors.

By an alternative pathway, non-ACE proteases can also convert ANG I to ANG II. Conversely, note that ANG I is not a specific substrate for ACE, which can cleave other peptides, including bradykinin (see pp. 553–554), enkephalins, and substance P.

Aminopeptidase A (also called angiotensinase A, or glutamyl aminopeptidase) further cleaves the aspartate-arginine bond on ANG II to produce the heptapeptide angiotensin III (ANG III, also called ANG-(2-8)), which has the sequence Arg-Val-Tyr-Ile-His-Pro-Phe. ANG III, like ANG II, can also bind to AT receptors.

Aminopeptidase B (also called angiotensinase B, or arginyl aminopeptidase) finally cleaves an arginine-valine bond on ANG III to produce the hexapeptide angiotensin IV (ANG IV, also called ANG-(3-8)). The sequence of ANG IV is Val-Tyr-Ile-His-Pro-Phe. This metabolite is inactive.

Finally, another ANG metabolite has received attention in recent years. ANG-(1-7) consists only of the first seven amino acids of ANG I*Asp-Arg-Val-Tyr-Ile-His-Pro. This heptapeptide can arise from ANG I by at least three routes:

image

Note that, by the above nomenclature, ANG I is ANG-(1-10), and ANG II is ANG-(1-8). The first and third pathways involve a new enzyme called ACE2. The second is catalyzed by any in a family of enzymes called neutral endopeptidases (NEPs). ANG-(1-7) can bind to a G protein–coupled receptor called the Mas receptor and—when acting on the cardiovascular system—can elicit effects opposite those of ANG II.

References

Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000;87:E1–E9.

Ferrario CM, Chappell MC. Novel angiotensin peptides. Cell Mol Life Sci. 2004;61:2720–2727.

Gurley SB, Allred A, Le TH, et al. Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Invest. 2006;116:2218–2225.

Yagil Y, Yagil C. Hypothesis: ACE2 modulates blood pressure in the mammalian organism. Hypertension. 2003;41:871–873.


*ANG-(1-7) is not to be confused with another heptapeptide metabolite of ANG II, namely, ANG III—also known as ANG-(2-8). ANG III has actions similar to those of ANG II, but is weaker (see pp. 553–554).

On the plasma membrane of the glomerulosa cell, ANG II binds to the AT1 receptor (type 1 ANG II receptor), which couples through the Gαq-mediated pathway to phospholipase C (PLC). Stimulation of PLC leads to the formation of diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3; see p. 58). DAG activates protein kinase C (PKC). IP3 triggers the release of Ca2+ from intracellular stores, thus causing a rise in [Ca2+]i, which activates Ca2+-dependent enzymes such as PKC and Ca2+-calmodulin–dependent protein kinases. These changes lead to depolarization of the glomerulosa cell's plasma membrane, opening of voltage-activated Ca2+ channels, and a sustained increase in Ca2+ influx from the extracellular space. This rise in [Ca2+]i is primarily responsible for triggering the synthesis (i.e., secretion) of aldosterone. Aldosterone secretion increases because the rise in [Ca2+]i facilitates the production of pregnenolone either by directly increasing the activity of SCC or by enhancing the delivery of cholesterol to the SCC enzyme in the mitochondria (see Fig. 50-2). In addition, increased [Ca2+]i also stimulates aldosterone synthase and in this manner enhances the conversion of corticosterone to aldosterone.

Potassium

An increase in extracellular K+ ([K+]o) has a direct action on the glomerulosa cell (see Fig. 50-6). Several K+ channels maintain the normal resting potential of these cells. imageN50-3 Thus, high [K+]o depolarizes the plasma membrane and opens voltage-gated Ca2+ channels. The result is an influx of Ca2+ and a rise in [Ca2+]i that stimulates the same two steps as ANG II—production of pregnenolone from cholesterol and conversion of corticosterone to aldosterone. Unlike the situation for ANG II, the [Ca2+]i increase induced by high [K+]o does not require activation of PLC or release of Ca2+ from the intracellular stores. Because increased [K+]o and ANG II both act by raising [Ca2+]i, they can act synergistically on glomerulosa cells.

N50-3

K+ Channel Mutations in Primary Hyperaldosteronism

Contributed by Emile Boulpaep, Walter Boron

Adrenal adenomas that produce aldosterone (from glomerulosa-like cells) can lead to severe “primary” hypertension. In a study by Choi and colleagues, 8 of 22 aldosterone-producing, unilateral adenomas had mutations in a G protein–activated, inwardly rectifying K+ channel called GIRK4 or KCNJ5 (see Table 6-2, family No. 2). The tissue samples were from the adenomas; the other cells in the body may not have had these mutations.

The authors also looked at a second group: a subset of patients with severe hypertension. Choi and colleagues found somatic mutations of KCNJ5—similar to the mutations in the adenomas—in people with bilateral adrenal hyperplasia and primary hyperaldosteronism. Thus, this is a form of hereditary hypertension.

These mutations in the two diseases cause a loss of selectivity for K+ over Na+ in the KCNJ5 channels. The resulting Na+ conductance depolarizes the glomerulosa cell, activating voltage-gated Ca2+ channels; this channel activation produces increased Ca2+ entry, a rise in [Ca2+]i, and thus an increase in constitutive aldosterone secretion. This cascade explains the primary hypertension. The presence of hyperplasia or neoplasia is consistent with the idea that KCNJ5 may play a role in cell proliferation.

Reference

Choi M, Scholl UI, Yue P, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011;331:768–772.

Adrenocorticotropic Hormone

ACTH stimulates aldosterone secretion by a pathway that is distinct from that of ANG II or high [K+]o (see Fig. 50-6), but has only a minor effect. As noted for fasciculata and reticularis cells on page 1023, in glomerulosa cells MC2R is coupled via a heterotrimeric G protein to adenylyl cyclase. Increases in ACTH raise [cAMP]i and activate PKA, which phosphorylates large numbers of cytosolic proteins. At some as-yet undefined level, these changes stimulate Ca2+ influx across the plasma membrane and enhance the synthesis and secretion of aldosterone. ACTH also enhances mineralocorticoid activity by a second mechanism: stimulation of the fasciculata cells to secrete cortisol, corticosterone, and DOC, all of which have weak mineralocorticoid activity. The hypertension seen in individuals who oversecrete ACTH appears to be mediated by the excess synthesis of these weak mineralocorticoids. Neither ANG II nor hyperkalemia affects the cAMP pathway triggered by ACTH (Box 50-4).

Box 50-4

Treating Hypertension by Attacking the Renin-Angiotensin-Aldosterone Axis

Because the renin-angiotensin-aldosterone axis plays an important role in maintaining extracellular volume and arterial pressure, pharmacologists have sought ways to disrupt this system to treat hypertension. Several agents acting on different parts of the axis are available. The aldosterone antagonists spironolactone and eplerenone are diuretics that block the action of aldosterone at the level of the MR. They are weak diuretics but are particularly useful in patients with treatment-resistant hypertension. For patients with resistant hypertension or congestive heart failure, aldosterone antagonists are usually added to one of the more common thiazide diuretics (see Box 40-3) to prevent K+ wasting.

ACE inhibitors have been available for a number of years and are among the safest and best-tolerated of all antihypertensive medications. These drugs also improve the quality of life and survival of patients with heart failure. Another class of drugs, the ARBs, specifically antagonize the AT1 receptor. These drugs offer a good alternative for those patients who cannot tolerate ACE inhibitors. Quite recently, inhibitors of renin activity have also become available, targeting yet another site within the renin-angiotensin system to treat hypertension.

Aldosterone exerts indirect negative feedback on the renin-angiotensin axis by increasing effective circulating volume and by lowering plasma [K+]

The feedback regulation exerted by aldosterone is indirect and occurs through its effects of both increasing salt retention (i.e., extracellular volume) and decreasing [K+]o.

Renin-Angiotensin Axis

As discussed beginning on page 841, a decrease in effective circulating volume stimulates the granular cells of the JGA of the kidney to increase their synthesis and release of renin, which increases the generation of ANG II and, therefore, aldosterone (see Fig. 50-6). The JGA is located at the glomerular pole of the nephron, between the afferent and efferent arterioles, where the early distal tubule comes in close proximity to its own glomerulus (Fig. 50-7). Histologically, the JGA comprises specialized epithelial cells of the distal tubule called macula densa cells, as well as specialized smooth-muscle cells of the afferent arteriole, which are called granular cells or juxtaglomerular cells. Macula densa cells and granular cells communicate by means of an extracellular matrix.

image

FIGURE 50-7 Structure of the JGA.

Decreases in effective circulating volume—or the associated decreases in systemic arterial pressure—stimulate renin release from the granular cells of the JGA in three ways discussed on page 841. Enhanced renin release leads to increased levels of ANG II and aldosterone. ANG II negatively feeds back on renin release directly by inhibiting renin release by granular cells (short-loop feedback). ANG II also negatively feeds back on renin release indirectly by acutely increasing systemic arterial pressure (see p. 553), thereby reducing the stimuli to release renin (see p. 841). Finally, aldosterone negatively feeds back on renin release more slowly by enhancing renal Na+ reabsorption (see p. 766) and thus increasing effective circulating blood volume and blood pressure. Therefore, ANG II and aldosterone complete the regulatory feedback circuit that governs the secretion of aldosterone.

Potassium

High plasma [K+] stimulates the glomerulosa cell in the adrenal cortex to synthesize and release aldosterone, which in turn stimulates the principal cells of the renal collecting duct to reabsorb more Na+ and excrete more K+ (see Fig. 50-6). This excretion of K+ causes plasma [K+] to fall toward normal. As a result, stimulation of glomerulosa cells declines, aldosterone secretion falls, and the negative-feedback loop is completed. This sequence of events (i.e., hyperkalemia → aldosterone secretion → K+ excretion) probably plays a vital role in preventing wide swings in plasma [K+] in response to episodic dietary intake of large K+ loads.

Role of Aldosterone in Normal Physiology

What, then, is the role of aldosterone in normal physiology? Presumably, the salt- and water-retaining properties of aldosterone are of greatest value in meeting the environmental stresses associated with limited availability of salt, water, or both. Such conditions are not prevalent in most Western societies, but they still exist in many developing countries and were probably universal in previous periods of human evolutionary history. In healthy, normotensive humans, blockade of aldosterone generation with ACE-inhibiting drugs reduces ANG II production and markedly decreases plasma aldosterone, but it causes only slight decreases in total-body Na+ and blood pressure. Redundant mechanisms for maintaining blood pressure probably prevent a larger blood pressure decrease. The reason for the mild effect on Na+ balance is probably an adaptive increase in salt intake; indeed, patients with adrenal cortical insufficiency frequently crave dietary salt. In contrast to the minor effects of low aldosterone on blood pressure and Na+ balance in physiologically normal people, the effects of blocking aldosterone production can be catastrophic for K+ balance; low aldosterone levels can result in life-threatening hyperkalemia. Potassium levels are carefully followed in patients receiving aldosterone antagonists, ACE inhibitors, angiotensin receptor blockers (ARBs), and renin inhibitors (see Box 50-4).

Role of Aldosterone in Disease

Aldosterone does play important roles in several pathological conditions. For example, in many patients with hypertension, ACE inhibitors or ARBs are effective in reducing blood pressure (see Box 50-4), a finding implying that their renin-angiotensin-aldosterone axis was overactive. In hypotension, as occurs with hemorrhage or dehydration, aldosterone secretion increases, thus raising effective circulating volume and blood pressure.

Aldosterone secretion also increases in congestive heart failure. However, the increased salt retention in this setting is inappropriate because it results in worsening edema formation. In this case, the increase in circulating aldosterone occurs despite pre-existing volume overload. The problem in congestive heart failure is that the JGA does not perceive the very real volume overload as an increase in effective circulating volume. Indeed, the reduced cardiac output in heart failure diminishes renal glomerular filtration, partly because of decreased arterial blood pressure and partly because of enhanced sympathetic nervous system activity, which constricts the afferent arterioles of the kidney. As a result, the kidney inappropriately assumes that the extracellular volume is decreased and stimulates the renin-angiotensin-aldosterone system.

Hyperaldosteronism was long thought to be an uncommon cause of hypertension. Now we recognize that hyperaldosteronism is responsible for ~10% of hypertension and for an even greater fraction of treatment-resistant hypertension. Primary hyperaldosteronism can result from either an isolated adrenal adenoma or bilateral adrenal hyperplasia; even more rarely, adrenal carcinoma can produce excess aldosterone. imageN50-4 In patients with adenomas of the glomerulosa cell, the disorder is called Conn syndrome. Hypertension and hypokalemia frequently develop in these patients. As would be expected from feedback regulation of the renin-angiotensin-aldosterone system, the plasma renin concentration is characteristically suppressed in this form of hypertension.

N50-4

Licorice as a Cause of Apparent Mineralocorticoid Excess

Contributed by Emile Boulpaep, Walter Boron

Glycyrrhizic acid is a chemical that consists of glycyrrhetinic acid (3-β-hydroxy-11-oxoolean-12-en-30-oic acid) conjugated to two glucuronic acid moieties. Glycyrrhizic acid is 150-fold sweeter than sucrose. It is naturally produced by the plant Glycyrrhiza glabra (Leguminosae) and is also present in European licorice. American licorice manufacturers generally substitute anise for glycyrrhizic acid.

Glycyrrhetinic acid and the glycyrrhetinic acid moiety of glycyrrhizic acid have the curious property that they inhibit the enzyme 11β-hydroxysteroid dehydrogenase (11βHSD). This enzyme converts cortisol into cortisone. imageN50-7 Because cortisol has a much higher affinity for the MR than does the breakdown product cortisone, inhibition of 11βHSD produces the same symptoms as a bona fide excess of mineralocorticoids. As described on page 766, this excess leads to Na+ retention and hypertension.

These compounds also inhibit 15-hydroxyprostaglandin dehydrogenase in the surface cells of the stomach and thereby increase levels of prostaglandins that protect the stomach from acid damage. This same action may also promote the release of mucus in the airway, which is why the active compounds of licorice have been used as expectorants.

True licorice has long been used as an herbal medicine.

Reference

Dalton L. What's that stuff? Licorice. Chem Eng News. 2002;80:32–37 http://pubs.acs.org/cen/whatstuff/stuff/8032licorice.html [Accessed October 2015].

N50-7

Reaction Catalyzed by 11β-Hydroxysteroid Dehydrogenase

Contributed by Eugene Barrett

Refer to Figure 50-2, specifically the cortisol molecule (4-pregnen-11β,17α,21-triol-3,20-dione), which has two highlighted hydroxyl groups—one on the C ring at position 11 and another on the D ring at position 17. The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) removes one H from the hydroxyl group at position 11 and another H from the same carbon, yielding a ketone group (O=C) at position 11. The product of this reaction is cortisone (4-pregnen-17α,21-diol-3,11,20-trione). Thus, the enzyme converts a triol (three hydroxyl groups)/dione (two ketone groups) to a diol (two hydroxyl groups)/trione (three ketone groups).