| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Outline of Final Research Achievements |
In this study, we tried to clarify the identification of esterases responsible for toxicities of two clinical drugs, acebutolol and ketoconazole. Lupus erythematosus and hepatotoxicity are known as side effects of acebutolol and ketoconazole, respectively. We found that acebutolol is hydrolyzed to acetolol by carboxyl esterase (CES) 2, followed by N-hydroxylation of acetolol by Cytochrome P450 (CYP) 2C19. Involvement of this metabolic pathway in acebutolol-induced toxicity was clarified using mice co-administered with CES and P450 inhibitors or inducers by evaluation of anti-nuclear antibody in plasma. Ketoconazole was specifically hydrolyzed to N-deacetylketoconazole by arylacetamide deacetylase (AADAC) in human liver. The involvement of AADAC in ketoconazole-induced toxicity was clarified using human hepatoma HepaRG cells with overexpression of human AADAC. These results would provide useful information for clinical and drug development.
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