ToxSci Advance Access originally published online on November 25, 2008
Toxicological Sciences 2009 107(2):385-393; 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
* Division of Environmental Health and Occupational Medicine
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli county 350, Taiwan, People’s Republic of China
Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan, People’s Republic of China
1 To whom correspondence should be addressed at Division of Environmental Health and Occupational Medicine, National Health Research Institutes, No. 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, People’s Republic of China. Fax: (886) 37-587406. E-mail: pplin{at}nhri.org.tw.
Received June 26, 2008; accepted November 13, 2008
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Abstract |
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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.
Key Words: arsenic; cytochrome P450 1A1; oxidative stress; aryl hydrocarbon receptor.