کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9002293 | 1118581 | 2005 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Activity profiles of deoxynucleoside kinases and 5â²-nucleotidases in cultured adipocytes and myoblastic cells: insights into mitochondrial toxicity of nucleoside analogs
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کلمات کلیدی
DMEM2′,3′-didehydro-2′,3′-dideoxythymidine3′-azido-2′,3′-dideoxythymidinedNKDNCNRTId4TAZTDGKdCK5′-NT - 5'-NTMitochondrial DNA - DNA میتوکندریاdeoxycytidine kinase - دگزوسی سیتیدین کینازDeoxyguanosine kinase - دیازویوانوزین کینازmtDNA - دیانای میتوکندریاییlipodystrophy - لیپودیستروفی پیش رونده، لیپودیستروفیnucleoside reverse transcriptase inhibitor - مهار کننده ترانس کپیکول معکوس نوکلئوزیدhuman immunodeficiency virus - ویروس نقص ایمنی انسانیHIV - ویروس نقص ایمنی انسانی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
داروشناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Nucleoside reverse transcriptase inhibitor (NRTI) treatment of HIV is associated with complications, including lipodystrophy (LD) and myopathy. Inhibition of mitochondrial DNA polymerase and depletion of mtDNA by NRTI triphosphates are believed to be key mechanisms in NRTI toxicity. Here, we determined the activities and mRNA levels of deoxynucleoside kinases (dNK) and 5â²-nucleotidases (5â²-NT) controlling the rate-limiting step in intracellular phosphorylation of NRTIs in cell models representing adipose, muscle tissue and peripheral blood cells using specific assays and Taqman RT-PCR. In vitro phosphorylation of 3â²-azido-2â²,3â²-dideoxythymidine (AZT) and 2â²,3â²-didehydro-2â²,3â²-dideoxythymidine (d4T) in extracts was also determined. 3T3-L1 adipocytes showed similar activity of mitochondrial thymidine kinase-2 (TK2) and deoxyguanosine kinase (dGK) but 3- to 36-fold lower levels of cytosolic deoxycytidine kinase (dCK), thymidine kinase-1 (TK1) and thymidine monophosphate kinase (TMPK) and higher levels of deoxyribonucleotidase activity compared to proliferating 3T3-L1. dCK, dGK and TK2 activities correlated with their mRNA levels in proliferating, resting and differentiating 3T3-L1. Differentiated L6 myoblasts had lower activities of cytosolic dNK's and TMPK, higher dGK and similar TK2 and deoxyribonucleotidases (dNT) activities compared to proliferating myoblasts. TK2 was the limiting dNK activity while dGK was predominant in adipocytes and myocytes. Activity profiles revealed limited capacity to phosphorylate dThd and dCyd in adipocytes and myocytes compared to proliferating cells and CEM lymphocytes. Phosphorylation of AZT and d4T was low in adipocytes and myocytes, and the presence of these analogs inhibited the phosphorylation of dThd by TK2 suggesting that mitochondrial toxicity of some NRTIs in adipocytes and myocytes is due to the depletion of normal mitochondrial dNTP pools.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 69, Issue 6, 15 March 2005, Pages 951-960
Journal: Biochemical Pharmacology - Volume 69, Issue 6, 15 March 2005, Pages 951-960
نویسندگان
Svetlana N. Rylova, Freidoun Albertioni, Gunnar Flygh, Staffan Eriksson,