کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5558523 1561148 2017 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Sibutramine provokes apoptosis of aortic endothelial cells through altered production of reactive oxygen and nitrogen species
ترجمه فارسی عنوان
سیبوترامین عامل آپوپتوز سلولهای اندوتلیال آئورت را از طریق تولید تغییر یافته از گونه های واکنش پذیر اکسیژن و نیتروژن
کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
چکیده انگلیسی


- Treatment with sibutramine, an anorexiant, induces endothelial cell apoptosis.
- The apoptotic mechanism includes induction of ROS and NO depletion.
- There is an inverse relationship between sibutramine cytotoxicity and its metabolism.

Overdose administration of sibutramine, a serotonin-noradrenalin reuptake inhibitor, is considered to elicit severe side effects including hypertension, whose pathogenic mechanism remains unclear. Here, we found that 48-h incubation with > 10 μM sibutramine provokes apoptosis of human aortic endothelial (HAE) cells. Treatment with the lethal concentration of sibutramine facilitated production of reactive oxygen species (ROS), altered expression of endoplasmic reticulum stress response genes (heat shock protein 70 and C/EBP homologous protein), and inactivated 26S proteasome-based proteolysis. The treatment also decreased cellular level of nitric oxide (NO) through lowering of expression and activity of endothelial NO synthase. These results suggest that ROS production and depletion of NO are crucial events in the apoptotic mechanism and may be linked to the pathogenesis of vasoconstriction elicited by the drug. Compared to sibutramine, its metabolites (N-desmethylsibutramine and N-didesmethylsibutramine) were much less cytotoxic to HAE cells, which hardly metabolized sibutramine. In contrast, both the drug and metabolites showed low cytotoxicity to hepatic HepG2 cells with high metabolic potency and expression of cytochrome P450 (CYP) 3A4. The cytotoxicity of sibutramine to HepG2 and Chang Liver cells was remarkably augmented by inhibition and knockdown of CYP3A4. This study also suggests an inverse relationship between sibutramine cytotoxicity and CYP3A4-mediated metabolism into the N-desmethyl metabolites.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology and Applied Pharmacology - Volume 314, 1 January 2017, Pages 1-11
نویسندگان
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