caa a22 4500 445854146 CHVBK 20180317145423.0 cr unu---uuuuu 170323e20111101xx s 000 0 eng 10.1007/s00204-011-0688-z doi (NATIONALLICENCE)springer-10.1007/s00204-011-0688-z Cytotoxic effects of hydroxylated fullerenes on isolated rat hepatocytes via mitochondrial dysfunction [Elektronische Daten] [Yoshio Nakagawa, Toshinari Suzuki, Hidemi Ishii, Dai Nakae, Akio Ogata] The cytotoxic effects of hydroxylated fullerenes, also termed fullerenols or fullerols [C60(OH)n], which are known nanomaterials and water-soluble fullerene derivatives, were studied in freshly isolated rat hepatocytes. The exposure of hepatocytes to C60(OH)24 caused not only concentration (0-0.25mM)- and time (0-3h)-dependent cell death accompanied by the formation of cell blebs, loss of cellular ATP, reduced glutathione (GSH), and protein thiol levels, but also the accumulation of glutathione disulfide and malondialdehyde, indicating lipid peroxidation. Of the other analogues examined, the cytotoxic effects of C60(OH)12 and fullerene C60 at a concentration of 0.125mM were less than those of C60(OH)24. The loss of mitochondrial membrane potential and generation of oxygen radical species in hepatocytes incubated with C60(OH)24 were greater than those with C60(OH)12 and fullerene C60. In the oxygen consumption of mitochondria isolated from rat liver, the ratios of state-3/state-4 respiration were more markedly decreased by C60(OH)24 and C60(OH)12 compared with C60. In addition, C60(OH)24 and C60(OH)12 resulted in the induction of the mitochondrial permeability transition (MPT), and the effects of C60(OH)12 were less than those of C60(OH)24. Taken collectively, these results indicate that (a) mitochondria are target organelles for fullerenols, which elicit cytotoxicity through mitochondrial failure related to the induction of the MPT, mitochondrial depolarization, and inhibition of ATP synthesis in the early stage and subsequently oxidation of GSH and protein thiols, and lipid peroxidation through oxidative stress at a later stage; and (b) the toxic effects of fullerenols may depend on the number of hydroxyl groups participating in fullerene in rat hepatocytes. Springer-Verlag, 2011 Hydroxylated fullerene nationallicence Fullerenols nationallicence Mitochondrial dysfunction nationallicence Oxidative stress nationallicence Cytotoxicity nationallicence Rat hepatocytes nationallicence DCHF-DA : 2′,7′-Dichlorodihydrofluorescein diacetate nationallicence DMSO : Dimethyl sulfoxide nationallicence GSH : Glutathione nationallicence GSSG : Glutathione disulfide nationallicence HEPES : N-(2-hydroxyethyl)-piperazine-N-(2-ethanesulfonic acid) nationallicence MDA : Malondialdehyde nationallicence MPT : Mitochondrial permeability transition nationallicence ROS : Reactive oxygen species nationallicence ΔΨ : Membrane potential nationallicence Nakagawa Yoshio Division of Pharmacology, Tokyo Metropolitan Institute of Public Health, 3-24-1, Hyakunin-cho, Shinjuku-ku, 169-0073, Tokyo, Japan aut Suzuki Toshinari Division of Water Environment, Tokyo Metropolitan Institute of Public Health, 3-24-1, Hyakunin-cho, Shinjuku-ku, 169-0073, Tokyo, Japan aut Ishii Hidemi Department of Molecular and Cellular Pathophysiology, Showa Pharmaceutical University, 3-3365, Higashi Tamagawa Gakuen, Machida, 194-8543, Tokyo, Japan aut Nakae Dai Division of Pharmacology, Tokyo Metropolitan Institute of Public Health, 3-24-1, Hyakunin-cho, Shinjuku-ku, 169-0073, Tokyo, Japan aut Ogata Akio Division of Pharmacology, Tokyo Metropolitan Institute of Public Health, 3-24-1, Hyakunin-cho, Shinjuku-ku, 169-0073, Tokyo, Japan aut Archives of Toxicology Springer-Verlag 85/11(2011-11-01), 1429-1440 0340-5761 85:11<1429 2011 85 204 https://doi.org/10.1007/s00204-011-0688-z text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00204-011-0688-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Nakagawa Yoshio Division of Pharmacology, Tokyo Metropolitan Institute of Public Health, 3-24-1, Hyakunin-cho, Shinjuku-ku, 169-0073, Tokyo, Japan aut NATIONALLICENCE 700 1- Suzuki Toshinari Division of Water Environment, Tokyo Metropolitan Institute of Public Health, 3-24-1, Hyakunin-cho, Shinjuku-ku, 169-0073, Tokyo, Japan aut NATIONALLICENCE 700 1- Ishii Hidemi Department of Molecular and Cellular Pathophysiology, Showa Pharmaceutical University, 3-3365, Higashi Tamagawa Gakuen, Machida, 194-8543, Tokyo, Japan aut NATIONALLICENCE 700 1- Nakae Dai Division of Pharmacology, Tokyo Metropolitan Institute of Public Health, 3-24-1, Hyakunin-cho, Shinjuku-ku, 169-0073, Tokyo, Japan aut NATIONALLICENCE 700 1- Ogata Akio Division of Pharmacology, Tokyo Metropolitan Institute of Public Health, 3-24-1, Hyakunin-cho, Shinjuku-ku, 169-0073, Tokyo, Japan aut NATIONALLICENCE 773 0- Archives of Toxicology Springer-Verlag 85/11(2011-11-01), 1429-1440 0340-5761 85:11<1429 2011 85 204 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer