Magnolol from Magnolia officinalis Inhibits 11β-Hydroxysteroid Dehydrogenase without Increases of Corticosterone and Thymocyte Apoptosis in Mice

Abstract

Magnolol is an 11β-hydroxysteroid dehydrogenase (11β-HSD) inhibitor contained in Magnolia officinalis which is used in Chinese remedies. We have reported that glycyrrhetinic acid, a strong 11β-HSD inhibitor isolated from licorice, induces apoptosis of murine thymocytes via accumulation of corticosterone. In this paper, we report that magnolol inhibited 11β-HSD without increases in the blood concentration of corticosterone and in thymocyte apoptosis in mice. Oxidative activities of the enzyme (from corticosterone to 11-dehydrocorticosterone) in liver, kidney and thymus in vitro were examined 24 h after a single administration of magnolol. Magnolol inhibited the enzyme activity in kidney (P < 0.0001) and thymus (P < 0.002), while the activity in liver was not affected. Blood concentrations of corticosterone in the magnolol-treated mice were unexpectedly lower than those in the control animals (P < 0.002). This means that the inhibition of 11β-HSD by magnolol did not increase the systemic level of corticosterone which is relevant to thymocyte apoptosis. Accordingly, our flow cytometric analysis of thymocytes after magnolol treatment showed no change in the number of apoptotic cells. We concluded that unlike glycyrrhetinic acid, magnolol selectively inhibited 11β-HSD in kidney and thymus but not in liver, so that the blood concentrations of corticosterone could not exceed the control level.

Magnolol - Magnolia officinalis - Magnoliaceae - glycyrrhetinic acid - 11β-hydroxysteroid dehydrogenase - corticosterone - thymocyte apoptosis

References

• 1 Haraguchi H, Ishikawa H, Shirataki N, Fukuda A. Antiperoxidative activity of neolignans from Magnolia obovata .  Journal of Pharmacy and Pharmacology. 1997;  49 209-12
• 2 Homma M, Oka K, Niitsuma T, Itoh H. A novel 11-beta-hydroxysteroid dehydrogenase inhibitor contained in saiboku-to, a herbal remedy for steroid-dependent bronchial asthma.  Journal of Pharmacy and Pharmacology. 1994;  46 305-9
• 3 Funder J W, Pearce P T, Smith R, Smith A I. Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated.  Science. 1988;  242 583-5
• 4 Walker B R. Organ-specific actions of 11-beta-hydroxysteroid dehydrogenase in humans: implications for the pathophysiology of hypertension.  Steroids. 1994;  59 84-9
• 5 Farese R V, Biglieri E G, Shackleton C H, Irony I, Gomez-Fontes R. Licorice-induced hypermineralocorticoidism.  New England Journal of Medicine. 1991;  325 1223-7
• 6 White P C, Mune T, Rogerson F M, Kayes K M, Agarwal A K. Molecular analysis of 11-beta-hydroxysteroid dehydrogenase and its role in the syndrome of apparent mineralocorticoid excess.  Steroids. 1997b;  62 83-8
• 7 Horigome H, Horigome A, Homma M, Hirano T, Oka K. Glycyrrhetinic acid induced apoptosis in thymocytes: impact of 11β-hydroxysteroid dehydrogenase inhibition.  American Journal of Physiology. 1999;  277 E624-30
• 8 Homma M, Oka K, Ikeshima K, Takahashi N, Niitsuma T, Fukuda T, Itoh H. Different effects of traditional Chinese medicines containing similar herbal constituents on prednisolone pharmacokinetics.  Journal of Pharmacy and Pharmacology. 1995;  47 687-92
• 9 Monder C, Stewart P M, Lakshmi V, Valentino R, Burt D, Edwards C R. Licorice inhibits corticosteroid 11 beta-dehydrogenase of rat kidney and liver: in vivo and in vitro studies.  Endocrinology. 1989;  125 1046-53
• 10 Kouno Y, Ishikura C, Takahashi N, Homma M, Oka K. Direct sample injection into the high-performance liquid chromatographic column in theophylline monitoring.  Journal of Chromatography. 1990;  515 321-7
• 11 Oka K, Noguchi M, Kitamura T, Shima S. Liquid chromatography and radioimmunoassay compared for determination of cortisol and corticosterone in plasma after a dexamethasone suppression test.  Clinical Chemistry. 1987;  33 1639-42
• 12 Fadok V A, Voelker D R, Campbell P A, Cohen J J, Bratton D L, Henson P M. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages.  Journal of Immunology. 1992;  148 2207-16
• 13 White P C, Mune T, Agarwal A K. 11 beta-Hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess.  Endocrine Review. 1997a;  18 135-56
• 14 Oka K, Hirano T, Homma M. Low-birth-weight hypertension via enzyme and receptor imprintings of glucocorticoid.  The Lancet. 1993;  342 303-4
• 15 MacKenzie M A, Hoefnagels W H, Jansen R W, Benraad T J, Kloppenborg P W. The influence of glycyrrhetinic acid on plasma cortisol and cortisone in healthy young volunteers.  Journal of Clinical Endocrinology and Metabolism. 1990;  70 1637-43
• 16 Homma M, Oka K, Yamada T, Niitsuma T, Ihto H, Takahashi N. A strategy for discovering biologically active compounds with high probability in traditional Chinese herb remedies: an application of saiboku-to in bronchial asthma.  Analytical Biochemistry. 1992;  202 179-87
• 17 Homma M, Oka K, Kobayashi H, Niitsuma T, Yamamoto S, Itoh H, Takahashi N. Impact of free magnolol excretions in asthmatic patients who responded well to saiboku-to, a Chinese herbal medicine.  Journal of Pharmacy Pharmacology. 1993a;  45 844-6
• 18 Homma M, Oka K, Niitsuma T, Itoh H. Pharmacokinetic evaluation of traditional Chinese herbal remedies.  The Lancet. 1993b;  341 1595
• 19 Watanabe K, Watanabe H, Goto Y, Yamaguchi M, Yamamoto N, Hagino K. Pharmacological properties of magnolol and honokiol extracted from Magnolia officinalis: central depressant effects.  Planta Medica. 1983;  49 103-8
• 20 Walker B R, Campbell J C, Fraser R, Stewart P M, Edwards C R. Mineralocorticoid excess and inhibition of 11-beta-hydroxysteroid dehydrogenase in patients with ectopic ACTH syndrome.  Clinical Endocrinology. 1992;  37 483-92
• 21 Taniguchi C, Homma M, Takano O, Hirano T, Oka K, Aoyagi Y, Niitsuma T, Hayashi T. Pharmacological effects of urinary products obtained after treatment with saiboku-to, a herbal medicine for bronchial asthma, on type IV allergic reaction.  Planta Medica. 2000;  66 607-11