title: Dysregulation of apoptosis by benzene metabolites and their relationships with carcinogenesis.
abstract: Benzene is a widely recognized human carcinogen, the effect of which is attributed to the production of reactive oxygen species (ROS) from its metabolites. Although there have been many reports on the relationship between DNA damage induced by benzene metabolites and carcinogenesis, only a report approached the subject by examining the benzene-induced dysregulation of apoptosis. Inhibition of apoptosis, aberrantly prolonging cell survival, may contribute to cancer by facilitating the insurgence of mutations and by creating a permissive environment for genetic instability. In this study, we examined the mechanism of antiapoptotic effects by benzene metabolites, p-benzoquinone (BQ) and hydroquinone (HQ), and their relationships with carcinogenesis. BQ and HQ inhibited the apoptotic death of NIH3T3 cells induced by both serum starvation and lack of an extracellular matrix (ECM). An antioxidant agent, N-acetylcysteine, significantly inhibited the antiapoptotic effects induced by benzene metabolites, indicating that the effects were mainly due to the production of ROS. Furthermore, BQ and HQ inhibited the in vitro caspase-3 activation, suggesting that the inhibition of caspase-3 activation due to ROS produced by BQ- and HQ-treatment was related to the suppression of apoptosis. The cells that escaped apoptosis could survive with the addition of serum and attachment to the ECM. Levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine were higher in the cells which survived after BQ- and HQ-treatment than in the normal cells. Furthermore, the cells treated with BQ and HQ showed greater proliferation than normal cells under low-serum conditions and anchorage-independent growth in soft agar. These findings suggested that benzene metabolites induced dysregulation of apoptosis due to caspase-3 inhibition, which contributes to carcinogenesis.
authors.affiliation: Laboratory of Radiation Biology, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan. ibuki@sea.u-shizuoka-ken.ac.jp
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ibuki
authors.forename: Rensuke
authors.initials: R
authors.lastname: Goto
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001554:Benzene / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D004789:Enzyme Activation; D006151:Guanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D006873:Hydroquinones / Q000494:pharmacology*; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000209:etiology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D006873:Hydroquinones; D017382:Reactive Oxygen Species; D006151:Guanosine; C046215:8-hydroxyguanosine; C004532:quinone; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D001554:Benzene; D000111:Acetylcysteine; C031927:hydroquinone