title: Ethambutol neutralizes lysosomes and causes lysosomal zinc accumulation.
abstract: Ethambutol is a common medicine used for the treatment of tuberculosis, which can have serious side effects, such as retinal and liver dysfunction. Although ethambutol has been reported to impair autophagic flux in rat retinal cells, the precise molecular mechanism remains unclear. Using various mammalian cell lines, we showed that ethambutol accumulated in autophagosomes and vacuolated lysosomes, with marked Zn(2+) accumulation. The enlarged lysosomes were neutralized and were infiltrated with Zn(2+) accumulations in the lysosomes, with simultaneous loss of acidification. These results suggest that EB neutralizes lysosomes leading to insufficient autophagy, implying that some of the adverse effects associated with EB in various organs may be of this mechanism.
authors: Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan.
authors: Daisuke
authors: D
authors: Yamada
authors: Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan. Electronic address: sai.bonsai007@gmail.com.
authors: Shinji
authors: S
authors: Saiki
authors: Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan; Department of Research and Therapeutics for Movement Disorders, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan.
authors: Norihiko
authors: N
authors: Furuya
authors: Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan.
authors: Kei-Ichi
authors: K
authors: Ishikawa
authors: Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan.
authors: Yoko
authors: Y
authors: Imamichi
authors: Laboratory of Biosignals and Response, Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors: Taiho
authors: T
authors: Kambe
authors: Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors: Tsutomu
authors: T
authors: Fujimura
authors: Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors: Takashi
authors: T
authors: Ueno
authors: Department of Cell Biology and Neuroscience, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan.
authors: Masato
authors: M
authors: Koike
authors: Department of Health and Nutrion, Tokiwa University, Ibaraki, Japan.
authors: Katsuhiko
authors: K
authors: Sumiyoshi
authors: Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan; Department of Research and Therapeutics for Movement Disorders, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan. Electronic address: nhattori@juntendo.ac.jp.
authors: Nobutaka
authors: N
authors: Hattori
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004977:Ethambutol / Q000008:administration & dosage*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D008657:Metabolic Clearance Rate / Q000187:drug effects; D010588:Phagosomes / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D051381:Rats; D015032:Zinc / Q000493:pharmacokinetics*
chemical_list: D000995:Antitubercular Agents; D004977:Ethambutol; D015032:Zinc
keywords: Autophagy; Ethambutol; Lysosome; Zinc