کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2571447 1128633 2008 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Role of hydrazine in isoniazid-induced hepatotoxicity in a hepatocyte inflammation model
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
Role of hydrazine in isoniazid-induced hepatotoxicity in a hepatocyte inflammation model
چکیده انگلیسی

Isoniazid is an anti-tuberculosis drug that can cause hepatotoxicity in 20% of patients that is usually associated with an inflammatory response. Hepatocytes when exposed to non-toxic levels of H2O2, to simulate H2O2 formation by inflammatory cells, became twice as sensitive to isoniazid toxicity. Isoniazid cytotoxicity was prevented by 1-aminobenzotriazole, a non-selective P450 inhibitor or by bis-p-nitrophenyl phosphate (BNPP), an esterase inhibitor. Moreover, the cytotoxicity of hydrazine, the metabolite formed by amidase-catalyzed hydrolysis of isoniazid, was increased 16-fold by a non-toxic H2O2-generating system. The acetylhydrazine metabolite was found to be much less cytotoxic than hydrazine in this hepatocyte inflammation model. Hydrazine, therefore, seems to be the isoniazid reactive metabolite in this inflammation model. The molecular mechanism of hydrazine-induced cytotoxicity was attributed to oxidative stress as reactive oxygen species (ROS) and protein carbonyl formation occurred before the onset of hepatocyte toxicity. Hydrazine toxicity also involved significant production of endogenous H2O2 which resulted in lysosomal membrane damage and leads to a collapse in mitochondrial membrane potential. These results implicated H2O2, a cellular mediator of inflammation, as a potential risk factor for the manifestation of adverse drug reactions, particularly those caused by hydrazine containing drugs.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology and Applied Pharmacology - Volume 229, Issue 1, 15 May 2008, Pages 94–101
نویسندگان
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