کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2514832 1118488 2007 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Existence of a distinct concentration window governing daunorubicin-induced mammalian liver mitotoxicity-implication for determining therapeutic window
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی داروشناسی
پیش نمایش صفحه اول مقاله
Existence of a distinct concentration window governing daunorubicin-induced mammalian liver mitotoxicity-implication for determining therapeutic window
چکیده انگلیسی
Daunorubicin (DNR) is a well known anticancer drug believed to act mainly by topoisomerase II inhibition and mitochondria-mediated free radical generation. Though several studies were dedicated to elucidate the mechanism of action of DNR, however the mechanism still remains illusive. DNR is reported to affect mitochondrial respiration. However, there are contradictory reports regarding DNR effect on oxygen consumption. Interestingly, DNR at low concentration (<10 μM) dose-dependently augments respiration but at higher concentration inhibits respiration. To investigate, if a concentration window exists in which the effect of DNR on mitochondria is optimum, dose-dependent effect of DNR on mitochondria was studied. DNR inhibited electron transfer and generates reactive oxygen species (ROS) at complex I and III but not at complex II. DNR-induced ROS generation was found instrumental in mitochondrial membrane potential collapse and mitochondrial permeability transition (MPT) opening. MPT closure reduced the observed respiratory burst. Thus, at lower DNR concentration, MPT opening leads to a sudden burst of respiration while at higher concentration electron transfer gets inhibited, therefore respiration gets repressed. We for the first time, provide a possible explanation for the reports regarding the differential regulation of respiration by DNR. Thus, further establishing the concept of concentration window and justifying the need for dose optimization for maximal therapeutic effect.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 74, Issue 6, 15 September 2007, Pages 821-830
نویسندگان
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