O 6-methylguanine-DNA methyltransferase (MGMT): Impact on cancer risk in response to tobacco smoke

摘要

Tobacco, smoked, snuffed and chewed, contains powerful mutagens and carcinogens. At least three of them, N-dimethylnitrosamine, N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, attack DNA at the O 6-position of guanine. The resulting O 6-alkylguanine adducts are repaired by the suicide enzyme O 6-methylguanine-DNA methyltransferase (MGMT), which is known to protect against the mutagenic, genotoxic and carcinogenic effects of monofunctional alkylating agents. While in rat liver MGMT was shown to be subject to regulation by genotoxic stress leading to adaptive changes in its activity, in humans evidence of adaptive modulation of MGMT levels is still lacking. Several polymorphisms are known, which are suspected to impact on the risk of developing cancer. In this review we focus on three questions: (a) Has tobacco consumption by smoking or chewing an impact on MGMT expression and MGMT promoter methylation in normal and tumor tissue? (b) Is there an association between MGMT polymorphisms and cancer risk and is this risk related to smoking? (c) Does MGMT protect against tobacco-associated cancer? There are several lines of evidence for an increase of MGMT activity in the normal tissue of smokers compared to non-smokers. Furthermore, in tumors developed in smokers a tendency towards an increase of MGMT expression was found. The data points to the possibility that agents in tobacco smoke are able to trigger upregulation of MGMT in normal and tumor tissue. For MGMT promoter methylation data is conflicting. There is some evidence for an association between MGMT polymorphisms and smoking-induced cancer risk. The key question whether or not MGMT protects against tobacco smoke-induced cancer is difficult to answer since prospective studies on smokers versus non-smokers are lacking and appropriate animal studies with MGMT transgenic mice exposed to the complex mixture of tobacco smoke have not been performed, which indicates the need for further explorations.