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
相关论文
共 50 条
  • [41] Selenium modifies the metabolism and toxicity of arsenic in primary rat hepatocytes
    Styblo, M
    Thomas, DJ
    TOXICOLOGY AND APPLIED PHARMACOLOGY, 2001, 172 (01) : 52 - 61
  • [42] Involvement of apoptosis in hydrazine induced toxicity in rat primary hepatocytes
    Hussain, SM
    Frazier, JM
    TOXICOLOGY IN VITRO, 2003, 17 (03) : 343 - 355
  • [43] Toxicity and uptake mechanism of cylindrospermopsin and lophyrotomin in primary rat hepatocytes
    Chong, MWK
    Wong, BSF
    Lam, PKS
    Shaw, GR
    Seawright, AA
    TOXICON, 2002, 40 (02) : 205 - 211
  • [44] Stereoselective Toxicity and Metabolism of Lactofen in Primary Hepatocytes From Rat
    Wang, Xinru
    Diao, Jinling
    Shen, Zhigang
    Zhu, Wentao
    Zhang, Ping
    Zhou, Zhiqiang
    CHIRALITY, 2013, 25 (11) : 743 - 750
  • [45] Ultrasound-guided direct delivery of 3-bromopyruvate blocks tumor progression in an orthotopic mouse model of human pancreatic cancer
    Shinichi Ota
    Jean-Francois H. Geschwind
    Manon Buijs
    Joost W. Wijlemans
    Byung Kook Kwak
    Shanmugasundaram Ganapathy-Kanniappan
    Targeted Oncology, 2013, 8 : 145 - 151
  • [46] Ultrasound-guided direct delivery of 3-bromopyruvate blocks tumor progression in an orthotopic mouse model of human pancreatic cancer
    Ota, Shinichi
    Geschwind, Jean-Francois H.
    Buijs, Manon
    Wijlemans, Joost W.
    Kwak, Byung Kook
    Ganapathy-Kanniappan, Shanmugasundaram
    TARGETED ONCOLOGY, 2013, 8 (02) : 145 - 151
  • [47] 3-Bromopyruvate reduces pancreatic tumor growth by damaging mitochondria and inhibiting glucose metabolism in both cell culture and mouse model
    Roy, Sanjit
    Dukic, Tijana
    Bhandary, Binny
    Molitoris, Jason
    Ko, Young H.
    Shukla, Hem D.
    CANCER RESEARCH, 2023, 83 (07)
  • [48] ISOLATION OF RAT HEPATOCYTES WITH EDTA AND THEIR METABOLIC FUNCTIONS IN PRIMARY CULTURE
    WANG, SR
    RENAUD, G
    INFANTE, J
    CATALA, D
    INFANTE, R
    IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY, 1985, 21 (09): : 526 - 530
  • [49] Metabolism and toxicity of coumarin on cultured human, rat, mouse and rabbit hepatocytes
    Ratanasavanh, D
    Lamiable, D
    Biour, M
    Guedes, Y
    Gersberg, M
    Leutenegger, E
    Riche, C
    FUNDAMENTAL & CLINICAL PHARMACOLOGY, 1996, 10 (06) : 504 - 510
  • [50] Metabolism of Enniatin B in primary mouse, rat and human hepatocytes
    Dubreil, E.
    Ivanova, L.
    Gendre, C.
    Mahdjoub, M.
    Fessard, V.
    Le Hegarat, L.
    Faeste, C.
    Henri, J.
    TOXICOLOGY LETTERS, 2024, 399 : S125 - S125