Topographical study of O(6)-alkylguanine DNA alkyltransferase repair activity and N7-methylguanine levels in resected lung tissue.
Authors
Crosbie, Philip A JHarrison, K
Shah, R
Watson, Amanda J
Agius, R
Barber, P
Margison, Geoffrey P
Povey, A
Affiliation
Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, UK; North West Lung Centre, University Hospital of South Manchester, Manchester M23 9LT, UK; Centre for Occupational and Environmental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PL, UK.Issue Date
2013-05-09
Metadata
Show full item recordAbstract
BACKGROUND: Tobacco specific nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are genotoxic alkylating agents found within cigarette smoke that induce lung adenocarcinomas in animal models. In humans, adenocarcinomas originate most frequently in the lung periphery. The aim of this study was to determine whether peripheral lung has increased susceptibility to the genotoxic effects of alkylating agents by comparing DNA alkylation damage (N7-methylguanine: N7-meG) and repair (O(6)-alkylguanine DNA alkyltransferase: MGMT) in peripheral relative to central lung tissue. METHODS: Macroscopically normal lung tissue, resected from patients undergoing surgery for lung cancer, was sampled at equidistant points from central to peripheral lung along a bronchus. N7-meG levels were determined using an immunoslotblot technique and MGMT activity with a [32P]-labelled oligodeoxynucleotide cleavage assay. RESULTS: A total of 20 subjects were recruited, 12 males and 8 females with a mean age of 68.7±5.8years. There were 14 former and 6 current smokers with a mean smoking exposure of 34.0±18.3packyears. N7-meG (mean 0.75±0.57/10(6)dG, n=65 samples from 14 patients) and MGMT repair (geometric mean 9.57±1.62fmol/μg DNA, n=79 samples from 16 patients) were detected in all samples assayed. MGMT activity increased towards the lung periphery (r=0.28, p=0.023; n=16) with a highly significant association in current (r=0.53, p=0.008; n=6) but not former smokers (r=0.13; p=0.41; n=10). No correlation was seen with N7-meG levels and lung position (r=-0.18; p=0.21; n=14). N7-meG levels were higher in current compared to former smokers reaching significance in two lung positions including peripheral lung (p=0.047). CONCLUSIONS: The findings in this study do not support the hypothesis that peripheral tissue is more susceptible to the genotoxic effects of alkylating agents than central lung tissue. In addition exposure to cigarette smoke reduced the level of MGMT in central bronchial tissue possibly through increased alkylating agent exposure.Citation
Topographical study of O(6)-alkylguanine DNA alkyltransferase repair activity and N7-methylguanine levels in resected lung tissue. 2013, 204 (2):98-104 Chem Biol InteractJournal
Chemico-Biological InteractionsDOI
10.1016/j.cbi.2013.04.013PubMed ID
23665414Type
ArticleLanguage
enISSN
1872-7786ae974a485f413a2113503eed53cd6c53
10.1016/j.cbi.2013.04.013
Scopus Count
Collections
Related articles
- Human colorectal mucosal O6-alkylguanine DNA-alkyltransferase activity and DNA-N7-methylguanine levels in colorectal adenoma cases and matched referents.
- Authors: Lees NP, Harrison KL, Hall CN, Margison GP, Povey AC
- Issue date: 2007 Mar
- Methyl DNA adducts, DNA repair, and hypoxanthine-guanine phosphoribosyl transferase mutations in peripheral white blood cells from patients with malignant melanoma treated with dacarbazine and hydroxyurea.
- Authors: Philip PA, Souliotis VL, Harris AL, Salisbury A, Tates AD, Mitchell K, van Delft JH, Ganesan TS, Kyrtopoulos SA
- Issue date: 1996 Feb
- Associations between smoking, GST genotypes and N7-methylguanine levels in DNA extracted from bronchial lavage cells.
- Authors: Lewis SJ, Cherry NM, Niven RM, Barber PV, Povey AC
- Issue date: 2004 Apr 11
- O(6)-methylguanine-DNA methyltransferase (MGMT): impact on cancer risk in response to tobacco smoke.
- Authors: Christmann M, Kaina B
- Issue date: 2012 Aug 1
- Lung cancer risk and variation in MGMT activity and sequence.
- Authors: Povey AC, Margison GP, Santibáñez-Koref MF
- Issue date: 2007 Aug 1