Smoking-related increase in O⁶-alkylguanine-DNA alkyltransferase activity in human lung tissue

Abstract

O6-Alkylguanine-DNA alkyltransferase (AGAT) activity was determined in macroscopically normal peripheral lung tissues from 122 patients undergoing lung surgery. AGAT activity of smokers was 1.4-fold higher than that of lifetime non-smokers (P = 0.030). Less than one year of abstinence from smoking did not cause a significant decrease in AGAT activity in former smokers, however, longer abstinence resulted in a decrease in AGAT activity to the level detected in lifetime non-smokers. There was no significant difference between levels of AGAT activity in lung cancer and noncancer patients. The results demonstrate that the level of AGAT activity in human peripheral lung tissue is influenced by smoking habits but does not have a diagnostic correlation to lung cancer.

Smoking is associated with a decrease of O6‐alkylguanine‐DNA alkyltransferase activity in bronchial epithelial cells

“…Such a lack of association has been reported for several tissues by several authors in different tissues. 11,12,15 In our study material, there was also no significant correlation with age. Previous studies using surgically resected lung tissues 12,15 or lymphocytes 25,26 have also failed to find an association between age and activity.…”

“…This is in contrast with a previous study, which reported smoking was associated with increased MGMT activity. 12 This difference may have resulted from the use of a more homogenous cell population in this study and the normalization procedure used. In this study, MGMT activity was normalized against DNA content rather than protein content, 12 and it is widely considered that normalization against DNA content is more appropriate.…”

“…12 This difference may have resulted from the use of a more homogenous cell population in this study and the normalization procedure used. In this study, MGMT activity was normalized against DNA content rather than protein content, 12 and it is widely considered that normalization against DNA content is more appropriate. 20 MGMT activity in BECs from smokers may be decreased because of a variety of reasons, including inactivation through the repair of O 6 -alkylguanine lesions, [5][6][7] direct inactivation of the active cysteine acceptor site by aldehydes or nitric oxide, for example, associated with cigarette smoke, 21,22 the direct effects of smoking on MGMT expression 23 or smoking-induced epigenetic changes.…”

“…8,10,11 Studies attempting to show whether in humans exposure to cigarette smoke causes an increase of MGMT activity in normal tissues have led to contradictory results. Some reports describe such increases, 12 while other studies report no association. [13][14][15] Several studies have attempted to find a direct correlation between MGMT activity in normal tissues and cancer susceptibility.…”

Inactivation of the DNA repair gene O6‐methylguanine‐DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B1‐DNA adducts and p53 mutation in hepatocellular carcinoma

“…31,32 However, MGMT inactivation may be an early event in tumorigenesis conferring an increased susceptibility to nitrosamines and other alkylating agents. 15 It was previously demonstrated that cytosine methylation enhances guanine alkylation by a variety of bulky carcinogens (benzo(a)pyrene diol epoxide, AFB 1 8,9-epoxide, benzo(g)chrysene diol epoxide and N-acetoxy-2-acetylaminofluorene).…”