title: Modulation of Ras signaling alters the toxicity of hydroquinone, a benzene metabolite and component of cigarette smoke.
abstract: BACKGROUND
  Benzene is an established human leukemogen, with a ubiquitous environmental presence leading to significant population exposure. In a genome-wide functional screen in the yeast Saccharomyces cerevisiae, inactivation of IRA2, a yeast ortholog of the human tumor suppressor gene NF1 (Neurofibromin), enhanced sensitivity to hydroquinone, an important benzene metabolite. Increased Ras signaling is implicated as a causal factor in the increased pre-disposition to leukemia of individuals with mutations in NF1.
  
  
  METHODS
  Growth inhibition of yeast by hydroquinone was assessed in mutant strains exhibiting varying levels of Ras activity. Subsequently, effects of hydroquinone on both genotoxicity (measured by micronucleus formation) and proliferation of WT and Nf1 null murine hematopoietic precursors were assessed.
  
  
  RESULTS
  Here we show that the Ras status of both yeast and mammalian cells modulates hydroquinone toxicity, indicating potential synergy between Ras signaling and benzene toxicity. Specifically, enhanced Ras signaling increases both hydroquinone-mediated growth inhibition in yeast and genotoxicity in mammalian hematopoetic precursors as measured by an in vitro erythroid micronucleus assay. Hydroquinone also increases proliferation of CFU-GM progenitor cells in mice with Nf1 null bone marrow relative to WT, the same cell type associated with benzene-associated leukemia.
  
  
  CONCLUSIONS
  Together our findings show that hydroquinone toxicity is modulated by Ras signaling. Individuals with abnormal Ras signaling could be more vulnerable to developing myeloid diseases after exposure to benzene. We note that hydroquinone is used cosmetically as a skin-bleaching agent, including by individuals with cafe-au-lait spots (which may be present in individuals with neurofibromatosis who have a mutation in NF1), which could be unadvisable given our findings.
authors.forename: Matthew
authors.initials: M
authors.lastname: North
authors.forename: Joe
authors.initials: J
authors.lastname: Shuga
authors.forename: Michele
authors.initials: M
authors.lastname: Fromowitz
authors.forename: Alexandre
authors.initials: A
authors.lastname: Loguinov
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
authors.forename: Luoping
authors.initials: L
authors.lastname: Zhang
authors.forename: Martyn T
authors.initials: MT
authors.lastname: Smith
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, California 94720, USA. vulpe@berkeley.edu.
authors.forename: Chris D
authors.initials: CD
authors.lastname: Vulpe
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D016514:Genes, Neurofibromatosis 1; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006873:Hydroquinones / Q000633:toxicity*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; D006873:Hydroquinones; C064960:IRA2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D012906:Smoke; C489014:RAS1 protein, S cerevisiae; D018631:ras Proteins; C031927:hydroquinone