title: Metabolic activation of carcinogenic ethylbenzene leads to oxidative DNA damage.
abstract: Ethylbenzene is carcinogenic to rats and mice, while it has no mutagenic activity. We have investigated whether ethylbenzene undergoes metabolic activation, leading to DNA damage. Ethylbenzene was metabolized to 1-phenylethanol, acetophenone, 2-ethylphenol and 4-ethylphenol by rat liver microsomes. Furthermore, 2-ethylphenol and 4-ethylphenol were metabolically transformed to ring-dihydroxylated metabolites such as ethylhydroquinone and 4-ethylcatechol, respectively. Experiment with 32P-labeled DNA fragment revealed that both ethylhydroquinone and 4-ethylcatechol caused DNA damage in the presence of Cu(II). These dihydroxylated compounds also induced the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine in calf thymus DNA in the presence of Cu(II). Catalase, methional and Cu(I)-specific chelator, bathocuproine, significantly (P<0.05) inhibited oxidative DNA damage, whereas free hydroxyl radical scavenger and superoxide dismutase did not. These results suggest that Cu(I) and H2O2 produced via oxidation of ethylhydroquinone and 4-ethylcatechol are involved in oxidative DNA damage. Addition of an endogenous reductant NADH dramatically enhanced 4-ethylcatechol-induced oxidative DNA damage, whereas ethylhydroquinone-induced DNA damage was slightly enhanced. Enhancing effect of NADH on oxidative DNA damage by 4-ethylcatechol may be explained by assuming that reactive species are generated from the redox cycle. In conclusion, these active dihydroxylated metabolites would be involved in the mechanism of carcinogenesis by ethylbenzene.
authors.affiliation: Department of Environmental and Molecular Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Midorikawa
authors.forename: Takafumi
authors.initials: T
authors.lastname: Uchida
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Chitose
authors.initials: C
authors.lastname: Toda
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Sakai
authors.forename: Koji
authors.initials: K
authors.lastname: Ueda
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hiraku
authors.forename: Mariko
authors.initials: M
authors.lastname: Murata
authors.forename: Shosuke
authors.initials: S
authors.lastname: Kawanishi
authors.forename: Nakao
authors.initials: N
authors.lastname: Kojima
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001555:Benzene Derivatives / Q000378:metabolism* / Q000494:pharmacology; D002273:Carcinogens / Q000378:metabolism* / Q000494:pharmacology; D002417:Cattle; D003300:Copper / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D006873:Hydroquinones / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D010618:Phenanthrolines; D010636:Phenols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013950:Thymus Gland
chemical_list: D001555:Benzene Derivatives; D002273:Carcinogens; D016166:Free Radical Scavengers; D006873:Hydroquinones; D010618:Phenanthrolines; D010636:Phenols; D009243:NAD; C495777:2-ethylphenol; D003300:Copper; D000080242:8-Hydroxy-2'-Deoxyguanosine; C495778:ethylhydroquinone; C002478:bathocuproine; C042291:4-ethylphenol; D003849:Deoxyguanosine; C004912:ethylbenzene