Localization of Cytochrome P4502E1 Enzyme in Normal and Cancerous Gastric Mucosa and Association with Its Genetic Polymorphism in Unoperated and Remnant Stomach

Abstract

Exposure to nitroso compounds and the activity of cytochrome P450 2E1 (CYP2E1), an activation enzyme for these carcinogens, are important factors in gastric carcinogenesis. Here, we investigated the potential correlation between genetic variation in CYP2E1 and its enzyme expression as detected with immunohistochemical (IHC) staining and cancer susceptibility in unoperated and remnant stomach. Expression of CYP2E1 in the stomach (n=117) was detected with IHC staining using a polyclonal anti-CYP2E1 antibody. Interindividual variation in CYP2E1 enzyme activity was then compared with genetic polymorphisms in the transcriptional flanking region of the CYP2E1 gene by restriction fragment length polymorphism (RFLP) detection using the Rsa I restriction enzyme. Genetic polymorphisms of Rsa I RFLP in CYP2E1 were investigated in 499 patients with gastric cancer (466 unoperated stomachs and 33 remnant stomachs) and 553 control patients with benign gastroduodenal diseases. Mucosal IHC staining for CYP2E1 was stronger in areas of intestinal metaplasia, particularly in endocrine cells, which stained consistently and strongly. Expression of CYP2E1 enzyme in areas of IHC staining were confirmed with Western blot analysis and showed a significant association between the degree of staining and the CYP2E1 genotype (p<0.01) in cancer tissues and in the foveolar epithelium of normal gastric mucosa. No association between specific CYP2E1 genotype and gastric cancer risk in the unoperated stomach was found in either the large study or the age- and gender-matched case-control study. However, the frequency of rare alleles (C1/C2 or C2/C2) was significantly higher in patients with cancer in the remnant stomach following gastrectomy than in controls subjects without cancer (odds ratio=2.8, 95% confidence interval=1.3-5.8) or those with primary gastric cancer (odds ratio=2.6, 95% confidence interval=1.3-5.5). CYP2E1 genetic polymorphisms might correlate with CYP2E1 enzyme expression levels in normal and cancerous gastric tissues. These polymorphisms do not influence the development of primary stomach cancer but may do so in specific conditions, such as the remnant stomach after gastrectomy.