title: Involvement of oxidative stress and activation of aryl hydrocarbon receptor in elevation of CYP1A1 expression and activity in lung cells and tissues by arsenic: an in vitro and in vivo study.
abstract: Epidemiological evidence indicated that there was a synergistic interaction between arsenic and cigarette smoke on enhancement of lung cancer risk. Benzo[a]pyrene (B[a]P), a component in cigarette smoke, is one of the most carcinogenic compounds known. Animal studies have demonstrated that there were increased benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) adduct formation and lung tumorigenesis in animals when they were coexposed to B[a]P and arsenic. Since BPDE adduct is a by-product of B[a]P metabolism, elevation of B[a]P metabolism by arsenic is suspected. However, the effects of arsenic on cytochrome P450 1A1 (CYP1A1) status (expression and activity), which is essential for B[a]P metabolism, either in lung cells or in lung tissues, are never demonstrated. We hypothesized that arsenic would enhance aryl hydrocarbon receptor (AhR) activation leading to CYP1A1 expression and activity in lung cells. Indeed, our present study successfully demonstrated the elevation of CYP1A1 messenger RNA expression in H1355 cells, a human lung adenocarcinoma cell line, as well as CYP1A1 expression and activity in lung tissues of arsenic-exposed mice. We further demonstrated that this elevation of CYP1A1 expression could be effectively blocked with AhR antagonist, 3',4'-dimethoxyflavone, indicating that the arsenic-induced CYP1A1 expression and activity were via AhR activation. Furthermore, we found that arsenic-induced AhR activation and -enhanced CYP1A1 expression can be further increased by a prooxidant, buthionine-(S,R)-sulfoximine, and suppressed by antioxidants, such as N-acetylcysteine and catalase. Our findings provided clear evidence that arsenic can enhance CYP1A1 expression and activity via AhR activation, and the arsenic-induced AhR activation is probably triggered by oxidative stress.
authors.affiliation: Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli county 350, Taiwan, [corrected] Republic of China.
authors.forename: Jui-Pin
authors.initials: JP
authors.lastname: Wu
authors.forename: Louis W
authors.initials: LW
authors.lastname: Chang
authors.forename: Hsien-Tsung
authors.initials: HT
authors.lastname: Yao
authors.forename: Han
authors.initials: H
authors.lastname: Chang
authors.forename: Hui-Ti
authors.initials: HT
authors.lastname: Tsai
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Tsai
authors.forename: Teng-Kuang
authors.initials: TK
authors.lastname: Yeh
authors.forename: Pinpin
authors.initials: P
authors.lastname: Lin
mesh_terms: D000818:Animals; D001151:Arsenic / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity*; D001564:Benzo(a)pyrene / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D017930:Genes, Reporter / Q000235:genetics; D066298:In Vitro Techniques; D008156:Luciferases / Q000235:genetics; D008168:Lung / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D001564:Benzo(a)pyrene; D008156:Luciferases; D019363:Cytochrome P-450 CYP1A1; D001151:Arsenic