Impaired mitochondrial functions contribute to 3-bromopyruvate toxicity in primary rat and mouse hepatocytes

被引:7
|
作者
Sobotka, Ondrej [1 ]
Endlicher, Rene [1 ,2 ]
Drahota, Zdenek [1 ,3 ]
Kucera, Otto [1 ]
Rychtrmoc, David [1 ]
Raad, Marjan [1 ]
Hakeem, Khurum [1 ]
Cervinkova, Zuzana [1 ]
机构
[1] Charles Univ Prague, Fac Med Hradec Kralove, Dept Physiol, Hradec Kralove, Czech Republic
[2] Charles Univ Prague, Fac Med Hradec Kralove, Dept Anat, Hradec Kralove, Czech Republic
[3] Czech Acad Sci, Inst Physiol, Prague, Czech Republic
关键词
3-bromopyruvate; Toxicity; Liver; Hepatocyte; Mitochondria; CANCER-CELLS; ANTICANCER AGENT; HEXOKINASE II; LIVER-CANCER; IN-VIVO; GLYCOLYSIS; DEATH; TARGETS; MODEL; ACETAMINOPHEN;
D O I
10.1007/s10863-016-9674-8
中图分类号
Q6 [生物物理学];
学科分类号
071011 ;
摘要
A compound with promising anticancer properties, 3-bromopyruvate (3-BP) is a synthetic derivative of a pyruvate molecule; however, its toxicity in non-malignant cells has not yet been fully elucidated. Therefore, we elected to study the effects of 3-BP on primary hepatocytes in monolayer cultures, permeabilized hepatocytes and isolated mitochondria. After a 1-h treatment with 100 mu M 3-BP cell viability of rat hepatocytes was decreased by 30 % as measured by the WST-1 test (p < 0.001); after 3-h exposure to aeyen200 mu M 3-BP lactate dehydrogenase leakage was increased (p < 0.001). Reactive oxygen species production was increased in the cell cultures after a 1-h treatment at concentrations aeyen100 mu mol/l (p < 0.01), and caspase 3 activity was increased after a 20-h incubation with 150 mu M and 200 mu M 3-BP (p < 0.001). This toxic effect of 3-BP was also proved using primary mouse hepatocytes. In isolated mitochondria, 3-BP induced a dose- and time-dependent decrease of mitochondrial membrane potential during a 10-min incubation both with Complex I substrates glutamate + malate or Complex II substrate succinate, although this decrease was more pronounced with the latter. We also measured the effect of 3-BP on respiration of isolated mitochondria. ADP-activated respiration was inhibited by 20 mu M 3-BP within 10 min. Similar effects were also found in permeabilized hepatocytes of both species.
引用
收藏
页码:363 / 373
页数:11
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