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

0469448 - FGÚ 2017 RIV US eng J - Článek v odborném periodiku
Sobotka, O. - Endlicher, R. - Drahota, Zdeněk - Kučera, O. - Rychtrmoc, D. - Raad, M. - Hakeem, K. - Červinková, Z.
Impaired mitochondrial functions contribute to 3-bromopyruvate toxicity in primary rat and mouse hepatocytes.
Journal of Bioenergetics and Biomembranes. Roč. 48, č. 4 (2016), s. 363-373. ISSN 0145-479X. E-ISSN 1573-6881
Institucionální podpora: RVO:67985823
Klíčová slova: 3-bromopyruvate * toxicity * liver * hepatocyte * mitochondria
Kód oboru RIV: EB - Genetika a molekulární biologie
Impakt faktor: 2.576, rok: 2016

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 μM 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 ≥200 μM 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 ≥100 μmol/l (p < 0.01), and caspase 3 activity was increased after a 20-h incubation with 150 μM and 200 μM 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 μM 3-BP within 10 min. Similar effects were also found in permeabilized hepatocytes of both species.
Trvalý link: http://hdl.handle.net/11104/0267247