The Effects of the Genetic Polymorphisms of N-acetyltransferase 2 and Glutathione S-transferase mu on the Development of Bladder Tumor

Kim, Wun Jae; Kim, Heon; Lee, Hyung Lae; Kim, Choung Soo; Choi, Han Yong

Abstract

PURPOSE: Activity of enzymes involved in the metabolism of various carcinogenic xenobiotics is one of the most important host factor for cancer occurrence. N-acetyltransferase (NAT) and glutathione S-transferase(GST) are enzymes which reduce the toxicity of activated carcinogenic metabolites. Slow N-acetylation and lack of glutathione S-transferase mu(GSTM1) were reported as risk factors of bladder tumor. Since the cause of bladder cancer is not fully explained by single risk factor, many kinds of enzymes would be involved in the metabolism of carcinogens excreted in urine. This study was performed to investigate whether the polymorphisms of N-acetyltransferase type 2(NAT2) and GSTM1 are risk factors of bladder tumor and to evaluate the effects of their interaction on bladder tumor development.
MATERIALS AND METHODS
113 bladder tumor and 221 non-cancer patients, hospitalized in the Chungbuk National University Hospital, Samsung Medical Center, and Asan Medical Center from March to December 1996 participated in this case-control study. Questionnaire interview was done and the genotypes of NAT2 and GSTM1 were identified using PCR methods with DNA extracted from the venous blood. The effects of the polymorphism of NAT2 and GSTM1 and their interaction on bladder cancer were statistically tested after controlling the other risk factors.
RESULTS
The frequencies of slow, intermediate, and rapid acetylators were 7.1%, 37.5%, and 55.4% for the cases, and 11.0%, 43.4%, and 45.7% for the controls, respectively. The risk of bladder tumor was not associated with the increase of NAT2 activity (chi2trend=3.16, p-value>0.05). GSTM1 was deleted in 69.6% of the cases and 55.9% of the controls (Chi2=5.86, p-value<0.05), and the odds ratio (95% CI) was 1.81 (1.12 - 2.93). Smoking history turned out to be insignificant as a risk factor of bladder tumor (OR=1.34, 95%CI: 0.78 - 2.31), and occupation could not be tested because of the extremely small number of occupational history related to the increase of bladder tumor. Medical history of tuberculosis and bronchial asthma were significant risk factors for bladder tumor, and their ORs (95% CI) were 3.61 (1.57-8.26) and 4.15 (1.61-10.75), respectively. In multiple logistic analysis controlling the effects of other risk factors, GSTM1 deletion (OR: 1.80, 95% CI: 1.07-3.05), and histories of tuberculosis (OR: 2.99, 95% CI: 1.22-7.32) and of bronchial asthma (OR: 3.38, 95% CI: 1.24-9.22) were the significant risk factors for bladder tumor, but slow acetylation was not.
CONCLUSIONS
These results suggest that GSTM1 deletion may be a significant risk factor of bladder tumor. The medications for tuberculosis and bronchial asthma could possibly cause bladder tumor, or immune mechanism might be involved in the development of bladder tumor.