title: Human CYP2E1-dependent and human sulfotransferase 1A1-modulated induction of micronuclei by benzene and its hydroxylated metabolites in Chinese hamster V79-derived cells.
abstract: Benzene is a ubiquitous environmental pollutant and a confirmed human carcinogen, which requires metabolic activation, primarily by CYP2E1, for most of its biological actions. Chromosome damages in benzene-exposed workers and rodents have been observed, and in their urine sulfo- and glucuronide-conjugates of phenol and hydroquinone were present. Yet, direct evidence for human CYP2E1-activated mutagenicity of benzene and the exact significance of phase II metabolism for inactivating benzene metabolites are still missing. In the present study, benzene and its oxidized metabolites (phenol, hydroquinone, catechol, 1,2,4-trihydroxybenzene and 1,4-benzoquinone) were investigated for induction of micronuclei in a V79-derived cell line genetically engineered for expression of both human CYP2E1 and human sulfotransferase (SULT) 1A1 (indicated by active micronuclei induction by 1-hydroxymethylpyrene). The results demonstrated concentration-dependent induction of micronuclei by benzene and phenol, though with lower potency or efficacy than the other metabolites. Inhibition of CYP2E1 by 1-aminobenzotriazole did not change the effect of benzoquinone, but completely abolished that of benzene and phenol, and attenuated that of the other compounds. Moreover, inhibition of SULT1A1 by pentachlorophenol potentiated the effects of benzene, hydroquinone, catechol and trihydroxybenzene. Ascorbic acid, a reducing and free radical-scavenging agent, significantly lowered the effects of hydroquinone, catechol, trihydroxybenzene as well as N-nitrosodimethylamine (a known CYP2E1-dependent promutagen), with that of benzoquinone unaffected. These results suggest that in addition to activating benzene and phenol, human CYP2E1 may further convert hydroquinone, catechol and trihydroxybenzene to more genotoxic metabolites, and sulfo-conjugation of the multi-hydroxylated metabolites of benzene by human SULT1A1 may represent an important detoxifying pathway.
authors.affiliation: Department of Toxicology, School of Public Health and Tropical Medicine, Southern Medical University, 1023 South Shatai Road, Guangzhou 510515, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Toxicology, School of Public Health and Tropical Medicine, Southern Medical University, 1023 South Shatai Road, Guangzhou 510515, China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Department of Toxicology, School of Public Health and Tropical Medicine, Southern Medical University, 1023 South Shatai Road, Guangzhou 510515, China.
authors.forename: Keqi
authors.initials: K
authors.lastname: Hu
authors.affiliation: Department of Toxicology, School of Public Health and Tropical Medicine, Southern Medical University, 1023 South Shatai Road, Guangzhou 510515, China.
authors.forename: Qinzhi
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of Toxicology, School of Public Health and Tropical Medicine, Southern Medical University, 1023 South Shatai Road, Guangzhou 510515, China. Electronic address: yungliu@126.com.
authors.forename: Yungang
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D015239:Arylsulfotransferase / Q000502:physiology*; D001554:Benzene / Q000378:metabolism / Q000633:toxicity*; D001555:Benzene Derivatives / Q000378:metabolism / Q000633:toxicity*; D002396:Catechols / Q000378:metabolism / Q000633:toxicity; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism / Q000633:toxicity; D017665:Hydroxyl Radical / Q000378:metabolism; D006900:Hydroxylation; D008658:Inactivation, Metabolic / Q000235:genetics; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D015162:Micronucleus Tests
chemical_list: D001555:Benzene Derivatives; D002396:Catechols; D006873:Hydroquinones; D017665:Hydroxyl Radical; D019392:Cytochrome P-450 CYP2E1; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; D001554:Benzene; C034221:catechol; C031927:hydroquinone
keywords: Benzene; CYP2E1; Micronuclei; Sulfotransferase (SULT)