Exploration for the real causative agents of licorice-induced pseudoaldosteronism

Abstract

I investigated the causative agents of licorice-induced pseudoaldosteronism, which is a frequent side effect of Japanese traditional Kampo medicines. Glycyrrhizin (GL), the main ingredient of licorice, is absorbed after being metabolized to glycyrrhetinic acid (GA) by intestinal bacteria, and then metabolized in liver to 3-monoglucuronyl-glycyrrhetinic acid (3MGA). In normal condition, 3MGA is excreted into bile via a multidrug resistance-related protein (Mrp) 2, therefore, 3MGA does not appear in blood circulation. However, under the dysfunction of Mrp2, 3MGA appears in the blood circulation and is excreted into the urine by not glomerular filtration but tubular secretion via organic anion transporter (OAT) 1 and 3. At this time, 3MGA inhibits type 2 11β-hydroxysteroid dehydrogenase (11βHSD2) in tubular cells to cause pseudoaldosteronism. Since GA is not the substrates of these transporters, GA cannot inhibit 11βHSD2 in tubular cells. Therefore, it was considered that 3MGA was the causative agents of licorice-induced pseudoaldosteronism. After that, I isolated and identified three other GL metabolites, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate-30-glucuronide (1), 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate (2), and 18β-glycyrrhetyl-3-O-sulfate (3) from the urine of Mrp2-deficient rats orally treated with GA, and found that their blood and urinary concentrations were much higher than 3MGA and that their pharmacokinetic behaviors were similar to 3MGA. 3MGA was not detected in the blood of patients with pseudoaldosteronism who developed rhabdomyolysis due to licorice, and compound 3 was detected at a high concentration. In addition, a multicenter retrospective study was conducted using the serum and urine of 97 patients who took Kampo medicines containing licorice. Of a total of 97 patients, 67 detected GA in the serum (median 122 nM, 5 nM–1.8 µM) and 68 detected compound 3 (median 239 nM, 2 nM–4.2 µM), and there were no cases of detection of GL, 3MGA, compounds 1, and 2. High blood concentrations of compound 3 were associated with low plasma renin activity, plasma aldosterone levels, and serum potassium levels. It is highly probable that compound 3 is the true causative agent of pseudoaldosteronism.

Treatment with Glycyrrhiza glabra Extract Induces Anxiolytic Effects Associated with Reduced Salt Preference and Changes in Barrier Protein Gene Expression

“…A proinflammatory effect of aldosterone has been described in several tissues [ 41 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ], including capillary endothelium [ 94 ]. Aldosterone acts synergistically at the innate immunity receptor, TLR4, with the TLR4 ligand lipopolysaccharide (LPS) to induce depression-like behavior [ 95 ]; therefore, the combined action of Glycyrrhiza glabra to reduce the RAAS [ 21 , 22 , 23 , 24 ] and antagonize the TLR4 receptor acts synergistically to reduce inflammation.…”

“…One of the 11β-HSD2 inhibitors is glycyrrhizin, an active component of licorice ( Glycyrrhiza glabra ). Inhibition of 11β-HSD2 results in a reduction in RAAS activity and an increase in blood pressure in animal models [ 21 , 22 ] and humans [ 21 , 23 , 24 ]. Treatment with glycyrrhizin induced antidepressant effects in two small studies in depressed patients [ 25 , 26 ].…”

Analysis of clinical factors associated with Kampo formula-induced pseudoaldosteronism based on self-reported information from the Japanese Adverse Drug Event Report database

“…Previous research indicated that glycyrrhizin, the chief component of Glycyrrhiza, and its metabolites cause pseudoaldosteronism by suppressing 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in renal distal tubular epithelial cells [ 13 , 24 ]. We identified concomitant hypertension as an independent factor linked to Kampo formula-induced pseudoaldosteronism.…”

“…type 2 (11β-HSD2) in renal distal tubular epithelial cells [13,24]. We identified concomitant hypertension as an independent factor linked to Kampo formula-induced pseudoaldosteronism.…”

Kampo medicines for supportive care of patients with cancer: A brief review

“…Evidence of the efficacy and safety of Kampo medicines for refractory symptoms in patients with cancer, such as anorexia, 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 fatigue, 11 and peripheral neuropathy, 12 , 13 , 14 , 15 , 16 , 17 , 18 has been accumulated. Adverse reactions to Kampo medicines are well documented, such as hepatic dysfunction, interstitial pneumonia, and pseudoaldosteronism, 19 , 20 , 21 , 22 but the incidence of these adverse reactions is extremely low. The long-term history of well-described Kampo combinations over hundreds of years, controlled quality of Kampo medicines, education of the doctors, and the small quantity of the individual herbal drug allow a safe-use of Kampo medicines alongside chemotherapy.…”