title: Benzene induces cytotoxicity without metabolic activation.
abstract: OBJECTIVE
  Benzene has been consistently associated with hematological disorders, including acute myeloid leukemia and aplastic anemia, but the mechanisms causing these disorders are still unclear. Various metabolites of benzene lead to toxicity through the production of reactive oxygen species (ROS), the inhibition of topoisomerase and DNA damage. However, benzene itself is considered to have no mutagenic or cytotoxic activity. In this study, we investigated the effects of benzene itself on a human myeloid cell line with or without benzene metabolizing enzyme inhibitors.
  
  
  METHODS
  A human myeloid cell line, HL-60, was exposed to benzene with or without cytochrome P450 2E1 or myeloperoxidase inhibitor. Cytotoxicity was evaluated in terms of global DNA methylation levels, induction of apoptosis, and ROS production.
  
  
  RESULTS
  Benzene did not change global DNA methylation levels. However, benzene itself increased the levels of apoptosis and ROS. This cytotoxicity did not change with the addition of benzene metabolizing enzyme inhibitors. Benzene itself increased the mRNA levels of oxidative stress-related genes and transcription factors of activator protein-1.
  
  
  CONCLUSIONS
  Benzene did not influence global DNA methylation in HL-60 cells, but had cytotoxic effects and changed gene expression levels. To elucidate the mechanisms of benzene toxicity, benzene itself as well as benzene metabolites must be investigated.
authors.affiliation: Department of Environmental Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Kimiko
authors.initials: K
authors.lastname: Izumo
authors.forename: Emiko
authors.initials: E
authors.lastname: Miyahara
authors.forename: Masahisa
authors.initials: M
authors.lastname: Horiuchi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Kawano
authors.forename: Toru
authors.initials: T
authors.lastname: Takeuchi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001554:Benzene / Q000633:toxicity*; D001711:Biotransformation; D019175:DNA Methylation / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1 / Q000235:genetics
chemical_list: D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D001554:Benzene