title: Cytotoxic effects of hydroxylated fullerenes on isolated rat hepatocytes via mitochondrial dysfunction.
abstract: The cytotoxic effects of hydroxylated fullerenes, also termed fullerenols or fullerols [C(60)(OH)(                            n                         )], which are known nanomaterials and water-soluble fullerene derivatives, were studied in freshly isolated rat hepatocytes. The exposure of hepatocytes to C(60)(OH)(24) caused not only concentration (0-0.25 mM)- and time (0-3 h)-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 C(60)(OH)(12) and fullerene C(60) at a concentration of 0.125 mM were less than those of C(60)(OH)(24). The loss of mitochondrial membrane potential and generation of oxygen radical species in hepatocytes incubated with C(60)(OH)(24) were greater than those with C(60)(OH)(12) and fullerene C(60). In the oxygen consumption of mitochondria isolated from rat liver, the ratios of state-3/state-4 respiration were more markedly decreased by C(60)(OH)(24) and C(60)(OH)(12) compared with C(60). In addition, C(60)(OH)(24) and C(60)(OH)(12) resulted in the induction of the mitochondrial permeability transition (MPT), and the effects of C(60)(OH)(12) were less than those of C(60)(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.
authors.affiliation: Division of Pharmacology, Tokyo Metropolitan Institute of Public Health, 3-24-1 Hyakunin-cho, Shinjuku-ku, Tokyo, Japan. Yoshio_1_Nakagawa@member.metro.tokyo.jp
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Toshinari
authors.initials: T
authors.lastname: Suzuki
authors.forename: Hidemi
authors.initials: H
authors.lastname: Ishii
authors.forename: Dai
authors.initials: D
authors.lastname: Nakae
authors.forename: Akio
authors.initials: A
authors.lastname: Ogata
mesh_terms: D000818:Animals; D016923:Cell Death; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured; D003603:Cytotoxins / Q000633:toxicity*; D037741:Fullerenes / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D006900:Hydroxylation; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects*; D018384:Oxidative Stress; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D003603:Cytotoxins; D037741:Fullerenes; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; C108127:fullerenol; D008315:Malondialdehyde; D005978:Glutathione; D019803:Glutathione Disulfide