کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5859429 1562348 2013 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Toxicity of thienopyridines on human neutrophil granulocytes and lymphocytes
ترجمه فارسی عنوان
سمیت تینوپیریدین ها بر گرانولوسیت ها و لنفوسیت های نوتروفیل انسان
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
چکیده انگلیسی


- All thienopyridines studied were toxic for neutrophil granulocytes and lymphocytes.
- Toxicity occurred at lower concentrations in granulocytes than in lymphocytes.
- Susceptibility of granulocytes was due to metabolites formed by myeloperoxidase.
- Metabolites and parent compounds induced apoptosis by a mitochondrial mechanism.

Thienopyridines can cause neutropenia and agranulocytosis. The aim of the current investigations was to compare cytotoxicity of ticlopidine, clopidogrel, clopidogrel carboxylate and prasugrel for human neutrophil granulocytes with the toxicity for lymphocytes and to investigate underlying mechanisms. For granulocytes, clopidogrel, ticlopidine, clopidogrel carboxylate and prasugrel were concentration-dependently toxic starting at 10 μM. Cytotoxicity could be prevented by the myeloperoxidase inhibitor rutin, but not by the cytochrome P450 inhibitor ketoconazole. All compounds were also toxic for lymphocytes, but cytotoxicity started at 100 μM and could not be prevented by rutin or ketoconazole. Granulocytes metabolized ticlopidine, clopidogrel, clopidogrel carboxylate and prasugrel, and metabolization was inhibited by rutin, but not by ketoconazole. Metabolism of these compounds by lymphocytes was much slower and could not be inhibited by ketoconazole or rutin. In neutrophils, all compounds investigated decreased the electrical potential across the inner mitochondrial membrane, were associated with cellular accumulation of ROS, mitochondrial loss of cytochrome c and induction of apoptosis starting at 10 μM. All of these effects could be inhibited by rutin, but not by ketoconazole. Similar findings were obtained in lymphocytes; but compared to neutrophils, the effects were detectable only at higher concentrations and were not inhibited by rutin. In conclusion, ticlopidine, clopidogrel, clopidogrel carboxylate and prasugrel are toxic for both granulocytes and lymphocytes. In granulocytes, cytotoxicity is more accentuated than in lymphocytes and depends on metabolization by myeloperoxidase. These findings suggest a mitochondrial mechanism for cytotoxicity for both myeloperoxidase-associated metabolites and, at higher concentrations, also for the parent compounds.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology - Volume 308, 7 June 2013, Pages 11-19
نویسندگان
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