Uridine Abrogates Mitochondrial Toxicity Related to Nucleoside Analogue Reverse Transcriptase Inhibitors in Hepg2 Cells
Uridine Abrogates Mitochondrial Toxicity Related to Nucleoside Analogue Reverse Transcriptase Inhibitors in Hepg2 Cells
复制标题
尿苷消除 Hepg2 细胞中与核苷类似物逆转录酶抑制剂相关的线粒体毒性
作者：
U. Walker;N. Venhoff;E. C. Koch;M. Olschewski;Josef Schneider;B. Setzer
目的探讨尿苷是否适用于核苷类似物逆转录酶抑制剂（NRTIs）的线粒体毒性。方法将人HepG 2-肝细胞暴露于含或不含尿苷的NRTI 25天。测定细胞生长、乳酸产生、细胞内脂质、线粒体DNA（mtDNA）以及呼吸链组分考克斯II（mtDNA编码）和考克斯IV（核编码）之间的比率。结果不含尿苷的扎西他滨（177 nM）可导致HepG 2细胞线粒体DNA严重缺失（至野生型线粒体DNA水平的8%），导致细胞增殖和考克斯II水平下降，乳酸和脂质积累增加。尿苷完全消除了扎西他滨对肝细胞增殖和正常化的乳酸合成，细胞内脂质和考克斯II水平的不利影响，通过调整mtDNA水平约65%的NRTI-未暴露的对照细胞。该效应具有剂量依赖性，在200 μM尿苷时达到最大值。尽管持续暴露于扎西他滨，但当加入到具有已建立的线粒体功能障碍的细胞中（扎西他滨15天）时，尿苷也迅速且完全恢复细胞功能。尿苷还使暴露于36 μM司他夫定的HepG 2细胞的细胞增殖正常化，并保护暴露于7 μM齐多夫定+8 μM拉米夫定（嘧啶类似物）的HepG 2-细胞，但未能改善暴露于11.8或118 μM去羟肌苷（嘌呤类似物）的细胞的细胞功能或mtDNA。结论嘧啶前体尿苷在体外可减轻抗逆转录病毒嘧啶NRTIs的线粒体毒性，补充嘧啶前体尿苷可能是预防或治疗HIV感染患者线粒体毒性的一种有前景的策略。
Objective To assess in vitro if uridine may be suitable to prevent or treat mitochondrial toxicity related to nucleoside analogue reverse transcriptase inhibitors (NRTIs). Methods Human HepG2-hepatocytes were exposed to NRTIs with or without uridine for 25 days. Cell growth, lactate production, intracellular lipids, mitochondrial DNA (mtDNA) and the ratio between the respiratory chain components COX II (mtDNA-encoded) and COX IV (nuclear-encoded) were measured. Results HepG2 cells exposed to zalcitabine (177 nM) without uridine developed a severe depletion of mtDNA (to 8% of wild-type mtDNA levels), resulting in a decline of cell proliferation and COX II levels, with increased lactate and lipid accumulation. Uridine fully abrogated the adverse effects of zalcitabine on hepatocyte proliferation and normalized lactate synthesis, intracellular lipids and COX II levels by adjusting mtDNA levels to about 65% of NRTI-unexposed control cells. This effect was dose-dependent, with a maximum at 200 μM of uridine. Uridine also rapidly and fully restored cell function when added to cells with established mitochondrial dysfunction (zalcitabine for 15 days) despite continued zalcitabine exposure. Uridine also normalized cell proliferation in HepG2 cells exposed to 36 μM of stavudine and protected HepG2-cells exposed to 7 μM of zidovudine + 8 μM of lamivudine (pyrimidine analogues), but failed to improve cell function or mtDNA in cells exposed to 11.8 or 118 μM of didanosine (a purine analogue). Conclusions The pyrimidine precursor uridine may attenuate the mitochondrial toxicity of antiretroviral pyrimidine NRTIs in vitro, and its supplementation may represent a promising strategy in the prevention or treatment of mitochondrial toxicities in HIV-infected patients.
Benzylacyclouridine 可逆转叠氮胸苷诱导的骨髓抑制，且不损害抗人类免疫缺陷病毒活性。
影响因子：
20.3
作者：
Calabresi,P;Falcone,A;StClair,MH;Wiemann,MC;Chu,SH;Darnowski,JW
通讯作者：
Darnowski,JW
抗人类免疫缺陷病毒 1 型治疗和周围神经病变：通过尿苷和丙酮酸预防 PC12 细胞（一种神经元模型）中的 2,3-双脱氧胞苷毒性。
影响因子：
3.6
作者：
Keilbaugh,SA;Hobbs,GA;Simpson,MV
通讯作者：
Simpson,MV
2,3-双脱氧肌苷 (ddI) 用于患有获得性免疫缺陷综合征或艾滋病相关综合症的患者。
DOI：
10.1056/nejm199005103221901
发表时间：
1990
期刊：
The New England journal of medicine
影响因子：
--
作者：
Lambert,JS;Seidlin,M;Reichman,RC;Plank,CS;Laverty,M;Morse,GD;Knupp,C;McLaren,C;Pettinelli,C;Valentine,FT
通讯作者：
Valentine,FT