ToxSci Advance Access published online on November 25, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn239
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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
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Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli county 350, Taiwan, ROC
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli county 350, Taiwan, ROC
Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC
* Correspondence: Pinpin Lin, Ph.D., Division of Environmental Health and Occupational Medicine, National Health Research Institutes, No. 35 Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC. Tel: 886-37246166; Fax: 886-37-587406; e-mail: pplin{at}nhri.org.tw
Received June 26, 2008; revision received November 10, 2008; accepted November 13, 2008
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Abstract |
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Epidemiological evidence indicated 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 co-exposed 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 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 AhR avtivation leading to cytochrome P450 1A1 (CYP1A1) expression and activity in lung cells. Indeed, our present study successfully demonstrated the elevation of CYP1A1 mRNA 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 aryl hydrocarbon receptor (AhR) antagonist, 3’,4’-dimethoxyflavone (DMF), indicating that the arsenic-induced CYP1A1 expression and activity were via AhR activation. Furtherrmore, we found that arsenic-induced AhR activation and enhanced CYP1A1 expression can be further increased by a pro-oxidant, buthionine-(S,R)-sulfoximine (BSO), and suppressed by antioxidants, such as N-acetylcysteine (NAC) 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.
Key Words: Arsenic; Cytochrome P450 1A1; Oxidative stress; Aryl hydrocarbon receptor (AhR).