title: Benzene metabolite 1,2,4-benzenetriol induces halogenated DNA and tyrosines representing halogenative stress in the HL-60 human myeloid cell line.
abstract: BACKGROUND
  Although benzene is known to be myelotoxic and to cause myeloid leukemia in humans, the mechanism has not been elucidated.
  
  
  OBJECTIVE
  We focused on 1,2,4-benzenetriol (BT), a benzene metabolite that generates reactive oxygen species (ROS) by autoxidation, to investigate the toxicity of benzene leading to leukemogenesis.
  
  
  METHODS
  After exposing HL-60 human myeloid cells to BT, we investigated the cellular effects, including apoptosis, ROS generation, DNA damage, and protein damage. We also investigated how the cellular effects of BT were modified by hydrogen peroxide (H2O2) scavenger catalase, hypochlorous acid (HOCl) scavenger methionine, and 4-aminobenzoic acid hydrazide (ABAH), a myeloperoxidase (MPO)-specific inhibitor.
  
  
  RESULTS
  BT increased the levels of apoptosis and ROS, including superoxide (O2•-), H2O2, HOCl, and the hydroxyl radical (•OH). Catalase, ABAH, and methionine each inhibited the increased apoptosis caused by BT, and catalase and ABAH inhibited increases in HOCl and •OH. Although BT exposure increased halogenated DNA, this increase was inhibited by catalase, methionine, and ABAH. BT exposure also increased the amount of halogenated tyrosines; however, it did not increase 8-oxo-deoxyguanosine.
  
  
  CONCLUSIONS
  We suggest that BT increases H2O2 intracellularly; this H2O2 is metabolized to HOCl by MPO, and this HOCl results in possibly cytotoxic binding of chlorine to DNA. Because myeloid cells copiously express MPO and because halogenated DNA may induce both genetic and epigenetic changes that contribute to carcinogenesis, halogenative stress may account for benzene-induced bone marrow disorders and myeloid leukemia.
authors.affiliation: Department of Environmental Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuraga-oka, Kagoshima, Japan. adu44150@ams.odn.ne.jp
authors.forename: Takuro
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Emiko
authors.initials: E
authors.lastname: Miyahara
authors.forename: Masahisa
authors.initials: M
authors.lastname: Horiuchi
authors.forename: Kimiko
authors.initials: K
authors.lastname: Izumo
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Yoshichika
authors.initials: Y
authors.lastname: Kawai
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Kawano
authors.forename: Toru
authors.initials: T
authors.lastname: Takeuchi
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002374:Catalase / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D054879:Halogenation / Q000187:drug effects; D006801:Humans; D006873:Hydroquinones / Q000633:toxicity*; D008715:Methionine / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D006873:Hydroquinones; D017382:Reactive Oxygen Species; C013038:hydroxyhydroquinone; D014443:Tyrosine; C034343:4-aminobenzhydrazide; D004247:DNA; D008715:Methionine; D002374:Catalase