دانلود رایگان مقاله لاتین هیدرولیز کتوکونازول داستیلاز آریل استامید از سایت الزویر
عنوان فارسی مقاله:
هیدرولیز کتوکونازول داستیلاز آریل استامید انسانی به دنبال سمیت کبدی
عنوان انگلیسی مقاله:
Human arylacetamide deacetylase hydrolyzes ketoconazole to trigger hepatocellular toxicity
سال انتشار : 2016
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مقدمه انگلیسی مقاله:
1. Introduction
Ketoconazole (KC), a synthetic imidazole antifungal agent, is effective against fungal infections and is widely used as a topical antifungal. In addition, KC is orally administered for Cushing’s syndrome [1,2], but hypoadrenalism may occur due to blocked adrenal steroidogenesis from inhibiting cytochrome P450s [3,4]. A major concern of oral ketoconazole is severe hepatotoxicity [5]. The US Food and Drug Administration recently limited usage of ketoconazole oral tablets, and the European Medicines Agency recommended no use of oral ketoconazole due to potential severe liver injury. In patients with KC-induced hepatotoxicity, hypersensitivity and eosinophilia were rarely observed with no allergic reactions. Therefore, cytotoxic mechanisms rather than immunotoxic mechanisms have been considered [5,6]. In general, not only the parent compound but also the metabolites should be considered when evaluating toxicity. KC can be hydrolyzed to deacetylketoconazole (DAK) by esterases and then metabolized to N-hydroxy DAK by flavin monooxygenase (FMO) (Fig. 1), which finally leads to a dialdehyde form [7–9]. Rodriguez and Acosta [10] evaluated the cytotoxicity of KC and DAK using rat hepatocytes by monitoring lactate dehydrogenase (LDH) leakage. They found that DAK showed a higher cytotoxicity than KC, and the cytotoxicity of DAK was exacerbated by n-octylamine, which is an activator of FMO enzymes. Next, the cytotoxicity was attenuated by methimazole, a competitive inhibitor of FMO enzymes, which implies that metabolism by esterases and FMO enzymes could be associated with ketoconazole-induced hepatotoxicity. It was reported that, among human FMO enzymes, human FMO1 and FMO3 could catalyze N-hydroxylation of DAK [9]. Yet the enzyme(s) responsible
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