کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2568146 1561170 2016 16 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen
ترجمه فارسی عنوان
مدل سلولی برای بررسی آسیب کبدی ناشی از مواد مخدر در بیماری کبد چرب غیر کلاسیک: کاربرد استامینوفن
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
چکیده انگلیسی


• Nonalcoholic fatty liver disease (NAFLD) is frequent in obese individuals.
• NAFLD can favor hepatotoxicity induced by some drugs including acetaminophen (APAP).
• A model of NAFLD was set up by using HepaRG cells incubated with stearate or oleate.
• Stearate-loaded HepaRG cells presented higher cytochrome P450 2E1 (CYP2E1) activity.
• APAP cytotoxicity was stronger in steatotic HepaRG cells with higher CYP2E1 activity.

Obesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presence of stearate with low (2.5 mM) or high (20 mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicity.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology and Applied Pharmacology - Volume 292, 1 February 2016, Pages 40–55
نویسندگان
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