Effects of cytochrome P450 (CYP) 2A6 gene deletion and CYP2E1 genotypes on gastric adenocarcinoma

Abstract

Cytochrome P450 (CYP) 2A6 and CYP2E1 are enzymes with a high ability to activate a nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to its potent and ultimate carcinogens. The polymorphic CYP2A6 and CYP2E1 have been implicated in increased susceptibility to certain malignancies. In our study, 120 Japanese patients with gastric adenocarcinoma and 158 healthy controls were compared for frequencies of CYP2A6 and CYP2E1 genotypes. The frequency with which the subjects carried homozygotes of the CYP2A6 gene deletion allele, which causes lack of the enzyme activity, was significantly higher in the gastric cancer patients than in the healthy control subjects (OR ‫؍‬ 3.14, 95% confidence interval (95% CI) ‫؍‬ 1.05-9.41). Subdividing gastric adenocarcinoma according to tumor differentiation, patients with the well-differentiated type were 4. Although gastric cancer incidence has fallen markedly over the past 50 years in industrialized nations, it remains the second leading cause of cancer death in Japan. Epidemiological and experimental evidence have indicated that excess salt intake, which promotes cell replication, increases gastric cancer risk. 1,2 There is considerable evidence to support the view that carcinogenic N-nitrosamine derivatives are important factors in human cancer, including gastric cancer. The chemical mechanisms of carcinogenesis by these nitrosamines in humans are therefore of considerable interest. 3,4 Numerous studies have shown that several cytochrome P450 (CYP) enzymes, particularly cytochrome P4502A6 (CYP2A6) and cytochrome P4502E1 (CYP2E1), catalyze metabolic activation of nitrosamine derivatives, including N-nitroso-dialkyiamines and tobacco-smoke-related nitrosamine. [5][6][7][8] Genetic polymorphisms for CYP2A6 have been described and 2 variant alleles associated with reduced activity have been identified. Variant 1 (CYP2A6*2) and Variant 2 (CYP2A6*3) are the results of amino acid exchanged for wildtype (CYP2A6*1). Recently, Kitagawa et al. 9 revealed that a novel deletion genotype variant of the CYP2A6 gene was one of the major polymorphic genes in Japanese lacking CYP2A6 activity.In addition, CYP2E1 represents a major CYP isoform in the human liver and is also expressed in extrahepatic tissue. This enzyme can be induced by certain chemicals, such as ethanol and large interindividual variations have been observed, suggesting that the variation may be due to genetic polymorphism. It was reported that RsaI polymorphism, which is located in the 5Ј-flanking region of CYP2E1 gene, has been shown to be associated with the transcriptional regulation of gene expression, resulting in different expression levels of the CYP2E1 mRNA. 6 CYP2E1 participated in the metabolic activation of various N-nitrosamines, including a potent tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. 8,10 Several recent reports have investigated the role of CYP2A6 genetic polymorphisms in tobacco dependence and lung cancer risk, with conflicting results. [11][12][13][14][15] Less ...

GSTT1,GSTM1andCYP2E1genetic polymorphisms in gastric cancer and chronic gastritis in a Brazilian population

“…On the other hand, other authors failed to demonstrate any statistically significant difference in the GSTM1 polymorphism distribution of gastric cancer patients and controls [24,26,32,36,52,55,56] . Several case-control studies also failed to find a significant association between the CYP2E1/PstI polymorphism and gastric cancer [23,24,26,34] . However, while Nishimoto et al [51] observed that the rare variant c2/c2 was associated with a reduced risk for gastric cancer in non-Japanese Brazilians, Wu et al [35] observed that the distribution of the c2/c2 genotype, detected by PstI or RsaI digestion, differed significantly between gastric cancer cases and controls.…”

“…The relationship between GSTT1, GSTM1 and CYP2E1 gene polymorphisms and the risk for gastric cancer is not obvious. Many investigations were conducted on Asian populations [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] . The Brazilian population is characterized by heterogeneous ethnic groups, emphasizing the need to investigate the frequency of these metabolizing genes and their association with gastric cancer.…”

CYP2E1 Genetic Polymorphism with Dietary, Tobacco, Alcohol Habits, H. pylori Infection Status and Susceptibility to Stomach Cancer in Mizoram, India

“…Kato et al, (1995) did not find any association between CYP2E1 RsaI genotype and stomach cancer. Tsukino et al, (2002);Park et al, (2003) and Darazy et al, (2011) also found no such association. In another study, Kato et al, (2011) reported that CYP2E1 RsaI polymorphisms do not influence the development of primary stomach cancer, but may do so in specific conditions, such as the remnant stomach after gastrectomy.…”

Genetic Factors Involved in the Genesis of Helicobacter Pylori-Induced Gastric Cancer

“…Usual case-control studies could provide the estimates for the final step (ie, literal carcinogenesis), when genotype frequency is different between gastric atrophy and gastric cancer, and the same among the uninfected, infected, and those with gastric atrophy. Table 5 lists the polymorphisms reported on gastric cancer risk, adopted from Gonzalez et al (Gonzalez et al, 2002) and recent studies (Ebert et al, 2005;Geddert et al, 2005;Li et al, 2005;Tsukino et al, 2002;Sugimoto et al, 2005;Gao et al, 2002;Wu et al, 2002;Goto et al, 2005;Lai et al, 2005a;Lee et al, 2004;Savage et al, 2004;Lai et al, 2005b;Lacasana-Navarro et al, 2006;Kim et al, 2005;Hamajima et al, 2002a;Duarte et al, 2005). The ORs are listed in case of being significant.…”

“…Biologically, the interactions of smoking, fresh vegetables/fruits and salty food with polymorphisms of carcinogen-metabolic enzyme and DNA repair enzymes are very plausible. cyclinD1 G870A Germany (Geddert, 2005) significant association (p=0.003) CYP1A1 Ile/Val China (Li, 2005) IleIle, CYP2C6 *1/*4 Japan (Tsukino, 2002) *1*1/*1*4, *4*4:3.14 (1.05-9.41) CYP2C19 *1/*2/*3 Japan (Sugimoto, 2005) * 1*1, no*1:1.98 (1.07-3.65)…”