Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

11 beta-OHSD is an enzyme complex consisting of 11 beta-DH, converting cortisol to cortisone in man and an 11-keto-reductase performing the reverse reaction. Congenital deficiency of 11 beta-DH should be considered in any child presenting with mineralocorticoid hypertension and suppression of the renin-angiotensin-aldosterone axis. The keystone to diagnosis is the demonstration of a reduced daily production rate of cortisol and an increase in its plasma half-life. In the majority of cases diagnosis can be made from a urinary steroid metabolite profile indicating a high excretion of cortisol relative to cortisone metabolites. Cortisol is the responsible mineralocorticoid, and as such treatment with the pure glucocorticoid dexamethasone will prevent life-threatening hypokalemia, although additional anti-hypertensive drugs are usually required to control blood pressure. Liquorice and carbenoxolone, for years thought to be direct "agonists" of the mineralocorticoid receptor, in fact cause sodium retention through inhibition of 11 beta-DH. The demonstration of 11 beta-DH activity in the vasculature raises the possibility that it locally modules access of glucocorticoids to mineralocorticoid and possibly glucocorticoid receptors in the vessel wall. It remains possible that subtle alterations of this cortisol-cortisone shuttle are responsible for other forms of hypertension which are currently classified under the umbrella diagnosis of essential hypertension.
 ...
PMID:The cortisol-cortisone shuttle and hypertension. 195 52

Metabolic and toxic effects caused by prolonged daily ingestion of Liquorice are well known in the literature. Such acquisition doesn't seem to be known enough by practitioners and by common people. Besides active substances such as Glycyrrhizin , Liquorice contains even steroids similar to the adrenocortical ones; among these the most important is Beta-Glycyrrhetinic acid. This one, in vivo and in vitro, produces salt and water retention by means of a "DOCA-like" mineral-corticoid mechanism, and clear suppression of the Renin-Angiotensin-Aldosterone axis. A low plasmatic level of Renin and Aldosterone is a common feature. The clinical picture in many ways is similar to the primary Aldosteronism and for this reason the above mentioned syndrome is usually called "Pseudoaldosteronism". Symptoms and signs can be classified into the following main groups: symptoms linked with water and salt retention: oedemas, hypertension, cardiac involvement. Symptoms linked with serum Potassium depletion: asthenia, paralysis (due to Potassium deficiency), myopathy with myoglobinuria. The diagnosis is essential based on an accurate pharmacological dietetic history, aimed to recognise an excessive use of Liquorice (pure or more often as substitute) in the screening of hypertension with or without hypopotassemia. Finally, the more or less quick normalisation of blood pressure and biochemical signs--as an "ex juvantibus" criterion--is the most important reason for the diagnosis. After a wide survey of the literature, the clinical and biological picture in four patients with chronic Liquorice ingestion and Pseudoaldosteronism syndrome is described.
 ...
PMID:[Pseudoaldosteronism caused by licorice. Review of the literature and description of 4 clinical cases]. 380 7

A 35-year-old man, who had been ingesting one or two bags of tablets of pure licorice daily (20-40 g/day) for about two years, developed an acute myopathy with high levels of serum muscle enzymes and the typical features of mineralocorticoid excess: serious hypokalemia, hypertension, metabolic alkalosis. Both plasma renin and serum aldosterone were below the normal values. Ultrastructural study of muscle showed only minor, aspecific changes. Glycyrrhizinic acid, a steroid-like glycoside contained in natural licorice, has a well-known mineralocorticoid activity but severe potassium depletion and rhabdomyolysis due to chronic licorice ingestion have rarely been reported. This case further indicates that such a possibility is to be considered in the differential diagnosis of a patient admitted because of acute flaccid tetraparesis and hypokalemia.
 ...
PMID:Acute hypokalemic myopathy due to chronic licorice ingestion: report of a case. 637 Sep 9

The authors report 2 cases of pseudohyperaldosteronism secondary to consumption of alcohol-free "pastis" in abstinent alcoholic cirrhotics. In both cases patients presented with ascites, edema, increased blood pressure and hypokalemic alkalosis. Except for hypokalemia, the disorders improved rapidly after withdrawal of the beverage. Glycyrrhizic acid, present in little amounts in the beverage, is presumably responsible for this syndrome. Patients with alcoholic cirrhosis would be particularly at risk. It is suggested that alcohol-free "pastis" could be responsible for ascites and edema in cirrhotic patients. This drinking habit should be looked for in abstinent cirrhotic patients with ascites, particularly in case of associated systemic hypertension.
 ...
PMID:[Pseudohyperaldosteronism induced by alcohol-free aniseed aperitif in alcoholic cirrhotic patients]. 652 26

In 1979, Ulick and New first coined the term Apparent Mineralocorticoid Excess (AME) for a syndrome of hypertension, hypokalaemia, suppressed renin-angiotensin-aldosterone axis and raised urinary ratio of 11 beta-hydroxy to 11-oxo metabolities of cortisol (suggesting a failure of conversion of cortisol to cortisone). In retrospect, the first case was described in 1974 and since then over 20 children have been reported worldwide but only one adult patient. The enzyme 11beta-hydroxysteroid dehydrogenase (11beta-OHSD) confers aldosterone specificity on intrinsically nonspecific kidney mineralocorticoid receptors by converting the active glucocorticoid cortisol to its inactive 11-oxo form (cortisone). Patients with AME have a deficiency of this enzyme which allows physiological levels of cortisol to flood mineralocorticoid receptors. Dexamethasone, by suppressing adrenal cortisol production, reverts the biochemistry but not usually the BP to normal. Liquorice inhibits 11beta-OHSD by virtue of its active ingredient glycyrrhetinic acid, resulting in an identical clinical picture. Renal 11beta-OHSD is the protagonist in AME but this enzyme is found in many other tissues including liver, placenta and vasculature, and one-third of essential hypertensives have deficient 11beta-OHSD. The placental isoform is thought to be the main barrier to maternal glucocorticoids reaching the fetus. The lowest rat placental 11beta-OHSD activity is found in the largest placentas corresponding to the smallest fetuses (presumably exposed to the highest glucocorticoid levels). This is the group which in humans are most at risk of developing hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Apparent mineralocorticoid excess. 806 85

Short-chain dehydrogenase reductase (SDR) enzymes influence mammalian reproduction, hypertension, neoplasia, and digestion. The three-dimensional structures of two members of the SDR family reveal the position of the conserved catalytic triad, a possible mechanism of keto-hydroxyl interconversion, the molecular mechanism of inhibition, and the basis for selectivity. Glycyrrhizic acid, the active ingredient in licorice, and its metabolite carbenoxolone are potent inhibitors of bacterial 3 alpha, 20 beta-hydroxysteroid dehydrogenase (3 alpha, 20 beta-HSD). The three-dimensional structure of the 3 alpha,20 beta-HSD carbenoxolone complex unequivocally verifies the postulated active site of the enzyme, shows that inhibition is a result of direct competition with the substrate for binding, and provides a plausible model for the mechanism of inhibition of 11 beta-hydroxysteroid dehydrogenase and 15-hydroxyprostaglandin dehydrogenase by carbenoxolone. The structure of human 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD) suggests the details of binding of estrone and 17 beta-estradiol in the active site of the enzyme and the possible roles of various amino acids in the catalytic cleft. The SDR family includes over 50 proteins from human, mammalian, insect, and bacterial sources. Only five residues are conserved in all members of the family, including the YXXXK sequence. X-ray crystal structures of five members of the family have been completed. When the alpha-carbon backbone of the cofactor binding domains of the five structures are superimposed, the conserved residues are at the core of the structure and in the cofactor binding domain, but not in the substrate binding pocket.
 ...
PMID:Structure and function of steroid dehydrogenases involved in hypertension, fertility, and cancer. 902 22

The enzyme 11 beta HSD catalyzes the interconversion of the biologically active cortisol and the biologically inactive cortisone. There are two distinct isozymes: 11 beta HSD type 1 is mainly expressed in liver and is a bidirectional enzyme, with both dehydrogenase and reductase activity. 11 beta HSD type 2 is mainly expressed in kidney and is a unidirectional enzyme with only dehydrogenase activity. 11 beta HSD type 2 protects the mineralocorticoid receptor from being activated by cortisol. Thus, specificity of this receptor in vivo is enzyme and not receptor mediated. The syndrome of apparent mineralocorticoid excess is caused by a congenital deficiency of 11 beta HSD type 2. Liquorice-induced hypertension is an example of an acquired defect in dehydrogenase activity of 11 beta HSD, caused by glycyrrhetinic acid. 11 beta HSD may play a role in the pathogenesis of 'essential' hypertension, obesity and type 1 diabetes mellitus. Angiotensin-converting enzyme inhibitors enhance dehydrogenase activity of 11 beta HSD, which may contribute to their natriuretic effect.
 ...
PMID:[11 beta-hydroxysteroid-dehydrogenase: characteristics and the clinical significance of a key enzyme in cortisol metabolism]. 1032 Dec 59

The ingestion of large quantities of glycyrrhizin, whether as a drug or a sweetener, is known, in susceptible subjects, to induce a syndrome similar to hypermineralcorticoidism, with bouts of hypertension, hypokaliaemia and rabdomyolysis, sometimes associated with severe renal failure and hypokaliaemia-induced arrythmias. Glycyrrhizin is also known to isomerize into the glycyrrhetic (or glycyrrhetinic) acids 18alpha- and 18beta-. In previous works, we reported that these metabolites cause bouts of hypertension and reduction in diuresis at low doses in the rat. In particular, the alpha isomer causes significant elimination of the calcium ion in the urine. The present findings confirm that 18alpha-glycyrrhetic acid is more toxic than either glycyrrhizin or the beta isomer. Histopathological study of tissue samples taken from rats treated with the alpha isomer also reveal selective damage to the myocardium with oedema, myolysis, apoptosis and blistering of the sarcoplasm. These effects begin to appear in the course of subchronic treatment, they manifest themselves in acute treatment and correlate closely with the electrocardiographic changes recorded in rats acutely treated with 18alpha-glycyrrhetic acid.
 ...
PMID:Correlation between high intake of glycyrrhizin and myolysis of the papillary muscles: an experimental in vivo study. 1060 84

Glycyrrhizic acid is currently of clinical interest for treatment of chronic hepatitis. It is also applied as a sweetener in food products and chewing tobacco. In some highly exposed subgroups of the population, serious side effects such as hypertension and electrolyte disturbances have been reported. In order to analyze the health risks of exposure to this compound, the kinetics of glycyrrhizic acid and its active metabolites were evaluated quantitatively. Glycyrrhizic acid and its metabolites are subject to complex kinetic processes, including enterohepatic cycling and presystemic metabolism. In humans, detailed information on these processes is often difficult to obtain. Therefore, a model was developed that describes the systemic and gastrointestinal tract kinetics of glycyrrhizic acid and its active metabolite glycyrrhetic acid in rats. Due to the physiologically based structure of the model, data from earlier in vitro and in vivo studies on absorption, enterohepatic cycling, and presystemic metabolism could be incorporated directly. The model demonstrates that glycyrrhizic acid and metabolites are transported efficiently from plasma to the bile, possibly by the hepatic transfer protein 3-alpha-hydroxysteroid dehydrogenase. Bacterial hydrolysis of the biliary excreted metabolites following reuptake of glycyrrhetic acid causes the observed delay in the terminal plasma clearance of glycyrrhetic acid. These mechanistic findings, derived from analysis of experimental data through physiologically based pharmacokinetic modeling, can eventually be used for a quantitative health risk assessment of human exposure to glycyrrhizic acid containing products.
 ...
PMID:Physiologically based pharmacokinetic modeling of glycyrrhizic acid, a compound subject to presystemic metabolism and enterohepatic cycling. 1065 46

Steroid dehydrogenase enzymes influence mammalian reproduction, hypertension, neoplasia, and digestion. The three-dimensional structures of steroid dehydrogenase enzymes reveal the position of the catalytic triad, a possible mechanism of keto-hydroxyl interconversion, a molecular mechanism of inhibition, and the basis for selectivity. Glycyrrhizic acid, the active ingredient in licorice, and its metabolite carbenoxolone are potent inhibitors of human 11 beta-hydroxysteroid dehydrogenase and bacterial 3 alpha, 20 beta-hydroxysteroid dehydrogenase (3 alpha, 20 beta-HSD). The three-dimensional structure of the 3 alpha, 20 beta-HSD carbenoxolone complex unequivocally verifies the postulated active site of the enzyme, shows that inhibition is a result of direct competition with the substrate for binding, and provides a plausible model for the mechanism of inhibition of 11 beta-hydroxysteroid dehydrogenase by carbenoxolone. The structure of the ternary complex of human 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD) with the cofactor NADP+ and the antiestrogen equilin reveals the details of binding of an inhibitor in the active site of the enzyme and the possible roles of various amino acids in the catalytic cleft. The short-chain dehydrogenase reductase (SDR) family includes these steroid dehydrogenase enzymes and more than 60 other proteins from human, mammalian, insect, and bacterial sources. Most members of the family contain the tyrosine and lysine of the catalytic triad in a YxxxK sequence. X-ray crystal structures of 13 members of the family have been completed. When the alpha-carbon backbone of the cofactor binding domains of the structures are superimposed, the conserved residues are at the core of the structure and in the cofactor binding domain, but not in the substrate binding pocket.
 ...
PMID:Steroid dehydrogenase structures, mechanism of action, and disease. 1066 97


1 2 3 Next >>