Carbonyl reduction of triadimefon by human and rodent 11¦Â-hydroxysteroid dehydrogenase 1

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• 作者：Arne Meyer^a ; Anna Vuorinen^b ; Agnieszka E. Zielinska^c ; Thierry Da Cunha^a ; Petra Strajhar^a ; Gareth G. Lavery^c ; Daniela Schuster^b ; Alex Odermatt^a ; ^{alex.odermatt@unibas.ch}
• 关键词：Triadimefon ; 11¦Â-Hydroxysteroid dehydrogenase ; Metabolism ; Liver microsomes ; Azole fungicide ; Molecular docking
• 刊名：Biochemical Pharmacology
• 出版年：2013
• 出版时间：1 May, 2013
• 年：2013
• 卷：85
• 期：9
• 页码：1370-1378
• 全文大小：868 K

文摘

11¦Â-Hydroxysteroid dehydrogenase 1 (11¦Â-HSD1) catalyzes the conversion of inactive 11-oxo glucocorticoids (endogenous cortisone, 11-dehydrocorticosterone and synthetic prednisone) to their potent 11¦Â-hydroxyl forms (cortisol, corticosterone and prednisolone). Besides, 11¦Â-HSD1 accepts several other substrates. Using rodent liver microsomes and the unspecific inhibitor glycyrrhetinic acid, it has been proposed earlier that 11¦Â-HSD1 catalyzes the reversible conversion of the fungicide triadimefon to triadimenol. In the present study, recombinant human, rat and mouse enzymes together with a highly selective 11¦Â-HSD1 inhibitor were applied to assess the role of 11¦Â-HSD1 in the reduction of triadimefon and to uncover species-specific differences. To further demonstrate the role of 11¦Â-HSD1 in the carbonyl reduction of triadimefon, microsomes from liver-specific 11¦Â-HSD1-deficient mice were employed. Molecular docking was applied to investigate substrate binding. The results revealed important species differences and demonstrated the irreversible 11¦Â-HSD1-dependent reduction of triadimefon. Human liver microsomes showed 4 and 8 times higher activity than rat and mouse liver microsomes. The apparent V_max/K_m of recombinant human 11¦Â-HSD1 was 5 and 15 times higher than that of mouse and rat 11¦Â-HSD1, respectively, indicating isoform-specific differences and different expression levels for the three species. Experiments using inhibitors and microsomes from 11¦Â-HSD1-deficient mice indicated that 11¦Â-HSD1 is the major if not only enzyme responsible for triadimenol formation. The IC₅₀ values of triadimefon and triadimenol for cortisone reduction suggested that exposure to these xenobiotica unlikely impairs the 11¦Â-HSD1-dependent glucocorticoid activation. However, elevated glucocorticoids during stress or upon pharmacological administration likely inhibit 11¦Â-HSD1-dependent metabolism of triadimefon in humans.