Modulation of Ras signaling alters the toxicity of hydroquinone, a benzene metabolite and component of cigarette smoke

BMC Cancer

Matthew North¹  Joe Shuga³  Michele Fromowitz³  Alexandre Loguinov¹  Kevin Shannon²  Luoping Zhang³  Martyn T Smith³  Chris D Vulpe¹ 

[1] Department of Nutritional Science and Toxicology, University of California, Berkeley, California 94720, USA

[2] Department of Pediatrics and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94115, USA

[3] Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, California 94720, USA

关键词: Yeast;    Ras;    NF1;    IRA2;    in vitro micronucleus assay;    Hydroquinone;   

Others  :  859167
DOI  :  10.1186/1471-2407-14-6

 received in 2013-05-30, accepted in 2013-12-27,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 North et al.; licensee BioMed Central Ltd.

【 图 表 】

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