Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The increased risk of rapid acetylator humans for the development of colorectal cancer has created interest in experimental animal models to study the relationship of N-acetyltransferase phenotype to colon cancer. Colon cytosols from inbred mouse lines were assayed for the ability to N-acetylate 2-aminofluorene to determine if the mouse model of the N-acetyltransferase polymorphism could be used to study this relationship. The results indicate that the colon acetylcoenzyme A: 2-aminofluorene-N-acetyltransferase activity parallels that of the liver. Colon activity from slow acetylator (A and B6.A) mouse lines is significantly lower than that of rapid acetylator (B6, B6.D, and A.B6) lines. p-Aminobenzoic acid N-acetyltransferase activity also differed between colon cytosols from rapid and slow acetylator strains. Isoniazid acetylation in colon and in liver did not differ between phenotypes. Northern blot analysis demonstrated the presence of mRNA for both NAT-1 and NAT-2 in mouse colon as well as in mouse liver. These results indicate that the N-acetyltransferase polymorphism is expressed in mouse colon when 2-aminofluorene or p-aminobenzoic acid is used as substrate and therefore the mouse may be a model for study of the effect of acetylator phenotype on development of colorectal cancer in humans.
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PMID:Polymorphic N-acetylation of 2-aminofluorene by cell-free colon extracts from inbred mice. 768 75

Acetylator phenotype is a common genetic trait in humans as well as other mammals. It results from the presence of several mutations in one of the genes encoding for arylamine N-acetyltransferase. The polymorphism has been associated with several disease states including colorectal cancer. Several epidemiological studies suggest that rapid acetylators are more susceptible to colorectal cancer than slow acetylators. Moreover, individuals that are both rapid acetylators and exhibit a high cytochrome P450 1A2 activity appear to have an even higher risk of colorectal cancer. These observations not only suggest an interesting genetic link to non-familial colon cancer but also suggest that carcinogens that are activated by N-acetyltransferase and cytochrome P450 1A2 may contribute to the etiology of this disease. Heterocyclic amines present in cooked food such as "well done" red meat are carcinogenic in experimental animals forming tumours in several target tissues including the small intestines. We have shown that human polymorphic N-acetyltransferase is present in human colon tissue and that it is capable of activating several heterocyclic amine carcinogens present in cooked food. These studies provide good circumstantial evidence that rapid acetylators may be predisposed to colorectal cancer.
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PMID:Role of acetylation in colorectal cancer. 769 97

Polymorphic N-acetyltransferase (NAT2), an enzyme present in the colon, may effect incidence of colon cancer. Individuals with NAT2 fast acetylator genotypes may have higher colon cancer risks due to faster conversion of certain carcinogens to mutagens. We determined NAT2 genotypes in 447 subjects with distal colon adenomas and in 487 controls. No significant increase in adenoma prevalence among fast acetylators was observed. However, there was a suggestion of ethnic differences in NAT2 effects. For example, white fast acetylators potentially had slightly increased risks for adenomas (odds ratio, 1.29; 95% confidence interval, 0.90-1.84), whereas fast acetylation was potentially protective among blacks (odds ratio, 0.64; 95% confidence interval, 0.32-1.28). The apparent difference between blacks and whites may simply reflect random variation around an overall null effect, or it could represent a real difference. There was preliminary evidence for a possible interaction between NAT2 and the glutathione transferase M1 null genotype. Smokers' adenoma prevalence was 10-fold higher for fast acetylators with the null genotype compared to slow acetylators without the null genotype. Large, multiethnic populations and analysis of combinations of genes for carcinogen metabolism may be needed to further assess the role of NAT2 in colorectal tumorigenesis.
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PMID:Acetylation polymorphism and prevalence of colorectal adenomas. 774 94

Although the etiology of colon cancer remains uncertain, an increasing body of epidemiologic evidence indicates that red meat consumption is an important risk factor. The cooking of red meat produces a class of potent experimental carcinogens, the heterocyclic aromatic amines (HAA). These induce cancers in several different sites, including the colon, in rats and mice. Other epidemiologic studies indicate that an individual's genetically determined metabolic phenotype (polymorphisms for N-acetyltransferase and N-hydroxylase) modulates the risk of colon cancer. Both N-acetyltransferase and N-hydroxylase are involved in the metabolism of HAA. An increased risk of colon cancer has been observed in rapid acetylators in four of five studies; further, in two of these the association was found only in meat eaters. The latter observation supports the hypothesis that HAA are involved in colon carcinogenesis. Considerable progress has been made in the study of the molecular pathogenesis of colon cancer, which typically entails the cumulation of several genetic events (mutations and deletions) in oncogenes and tumor suppressor genes. It would now be a crucial contribution to elucidating the causation of colon cancer to show that such mutations are induced in human colonic mucosa by food-borne heterocyclic aromatic amines.
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PMID:Interplay between heterocyclic amines in cooked meat and metabolic phenotype in the etiology of colon cancer. 881 37

Some previous studies have suggested that the fast phenotype of the N-acetyltransferase NAT2 may confer susceptibility to colorectal cancer because of greater activation of dietary heterocyclic amines, particularly in individuals who also consume well-done red meat, but other studies have not supported this. We describe a large case-control study examining the interaction between dietary, smoking and drinking habits, and acetylation genotype in relation to susceptibility to colorectal cancer. One-hundred-and-seventy-four incident cases and 174 matched controls were recruited. Genotyping for polymorphisms in NAT2 was performed using a method that detects >95% of slow alleles and data on personal habits were collected using a standardized questionnaire. We found no difference in the frequency of the fast acetylator genotype between cases and controls [odds ratio = 0.95 (95% CI 0.61-1.49)], and analysis by sex, age and site also revealed no difference in acetylator genotype. There was, however, considerable heterogeneity in dietary risk factors between fast and slow acetylators. Analysis by acetylator type shows that recent smoking was more frequent in slow acetylator cases than matched controls [OR = 2.31 (1.16-4.6)] and that heavy alcohol consumption was also more frequent in the slow acetylator cases than controls [OR = 2.5 (1.02-7.29)]. In contrast, frequent fried meat intake was seen more frequently in fast acetylator cases than matched controls [OR = 6.0 (1.34-55)]. The odds ratio for the combination of fast acetylator status and frequent fried meat consumption in cases was 6.04 (1.6-26). Our study suggests that there may be different risk factors for colorectal cancer in slow and fast acetylators, and reveals a new observation that slow acetylators may be at risk of colon cancer from smoking. In our community, the overall effect of acetylator status on colorectal cancer risk is neutral.
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PMID:Relationship between acetylator status, smoking, and diet and colorectal cancer risk in the north-east of England. 923 Feb 78

Here we report that colorectal cancer patients show a markedly higher frequency (3-fold) of wild-type NAT2*4 allele homozygotes than the control population. However, a marked difference in NAT2*4/NAT2*4 genotype frequency associated with the patients gender was observed pointing to a male-specific effect of this genotype as a risk factor in colon cancer. The arylamine-N-acetyltransferase (E.C. 2.3.1.5.) NAT2, a phase II detoxification enzyme, has been implicated in procarcinogen activation, namely from food contained arylamines, cigarette smoking, as well as environmental amines of various types. NAT2 is encoded by a polymorphic gene presenting several allelic variants encoding partially inactive enzymes expressed in human liver and colon. Epidemiological studies based on phenotype determination have long indicated the importance of the NAT2 active phenotype as a susceptibility factor in colorectal cancer. In the present study we investigated the NAT2 allelic frequencies and genotype distribution in a group of 114 unrelated colorectal cancer patients, in parallel with 201 healthy Portuguese subjects. We first demonstrate that the frequency of the wild-type NAT2*4 allele in the Portuguese sample population (23.4%) does not significantly differ from the values described for other Europeans. Besides the 3-fold higher frequency of NAT2*4 homozygotes found in colorectal cancer subjects, the NAT2*4/NAT2*5A compound genotype, known to determine a faster acetylator phenotype than other heterozygotic combinations, also increased by the same order of magnitude. These two genotypes represent 32% of the patients population versus 11% of the healthy controls. Taken together, our results strongly indicate that NAT2 genotype, particularly NAT2*4 allele zygosity, constitutes an individual susceptibility trait associated with sporadic colorectal cancer development, probably due to the local dietary habits in Portugal.
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PMID:Increased frequency of wild-type arylamine-N-acetyltransferase allele NAT2*4 homozygotes in Portuguese patients with colorectal cancer. 947 90

There are two entities in the predisposition for colorectal cancer. One is the hereditary colorectal cancers which include familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC), and others. In the case of these hereditary diseases, genetic testing to detect germline mutation in the causative gene in family members is useful for identifying possible gene carriers. For the diagnosis of HNPCC, the present clinical criteria are not sufficient and analysis of DNA replication error (RER) could be useful. Another entity is genetic sensitivity to environmental carcinogens. In particular, the polymorphism of the genes encoding drug-metabolizing enzymes has been shown to be important in recent years. The fast acetylator genotype of N-acetyltransferase (NAT) genes and the null genotype of the glutathione S-transferase M1 gene have been reported to be associated with increased risk of colon cancer. In the strategy against colon cancer, it is extremely important to identify high-risk individuals so that we can prevent cancers or detect them in earlier stages.
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PMID:[Molecular biological assessment of susceptibility to colorectal cancer]. 969 70

It has become clear that several polymorphisms of human drug-metabolizing enzymes influence an individual's susceptibility for chemical carcinogenesis. This review gives an overview on relevant polymorphisms of four families of drug-metabolizing enzymes. Rapid acetylators (with respect to N-acetyltransferase NAT2) were shown to have an increased risk of colon cancer, but a decreased risk of bladder cancer. In addition an association between a NAT1 variant allele (NAT*10, due to mutations in the polyadenylation site causing approximately two fold higher activity) and colorectal cancer among NAT2 rapid acetylators was observed, suggesting a possible interaction between NAT1 and NAT2. Glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) are polymorphic due to large deletions in the structural gene. Meta-analysis of 12 case-control studies demonstrated a significant association between the homozygous deletion of GSTM1 (GSTM1-0) and lung cancer (odds ratio: 1.41; 95% CI: 1.23-1.61). Combination of GSTM1-0 with two allelic variants of cytochrome P4501A1 (CYP1A1), CYP1A1 m2/m2 and CYP1A1 Val/Val further increases the risk for lung cancer. Indirect mechanisms by which deletion of GSTM1 increases risk for lung cancer may include GSTM1-0 associated decreased expression of GST M3 and increased activity of CYP1A1 and 1A2. Combination of GST M1-0 and NAT2 slow acetylation was associated with markedly increased risk for lung cancer (odds ratio: 7.8; 95% CI: 1.4-78.7). In addition GSTM1-0 is clearly associated with bladder cancer and possibly also with colorectal, hepatocellular, gastric, esophageal (interaction with CYP1A1), head and neck as well as cutaneous cancer. In individuals with the GSTT1-0 genotype more chromosomal aberrations and sister chromatid exchanges (SCEs) were observed after exposure to 1,3-butadiene or various haloalkanes or haloalkenes. Evidence for an association between GSTT1-0 and myelodysplastic syndrome and acute lymphoblastic leukemia has been presented. A polymorphic site of GSTP1 (valine to isoleucine at codon 104) decreases activity to several carcinogenic diol epoxides and was associated with testicular, bladder and lung cancer. Microsomal expoxide hydrolase (mEH) is polymorphic due to amino acid variation at residues 113 and 139. Polymorphic variants of mEH were associated with hepatocellular cancer (His-113 allele), ovarian cancer (Tyr-113 allele) and chronic obstructive pulmonary disease (His-113 allele). Three human sulfotransferases (STs) are regulated by genetic polymorphisms (hDHEAST, hM-PST, TS PST). Since a large number of environmental mutagens are activated by STs an association with human cancer risk might be expected.
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PMID:Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase and sulfotransferases: influence on cancer susceptibility. 1002 93

The acetylation polymorphism, discovered 40 years ago, holds a special place as one of the first described examples of a pharmacogenetic defect affecting xenobiotic biotransformation capacity in human populations. The genetically determined N-acetyltransferase activity is involved in activation/inactivation reactions of numerous xenobiotics. Therefore, it has been suggested that slow acetylator status may modify the individual responses to various chemicals. In humans, two genes, NAT1 and NAT2, are responsible for N-acetyltransferase activity. To date several allelic variants of both NAT1 and NAT2 have been detected, and it has been suggested that some of them modify individual susceptibility to cancer. Slow NAT2 acetylation capacity has been suggested as conferring increased risk of bladder, breast, liver and lung cancers, and decreased risk of colon cancer, whereas a prominent change in the NAT1 gene, putatively associated with increased NAT1 activity, has been suggested as increasing the risk of bladder and colon cancer and decreasing that of lung cancer. While three of the NAT2 variants have been shown to account for most of the slow NAT2 acetylator genotypes in Caucasians, less complete data are available on how the NAT1 variants modify NAT1 activity in vivo. This review discusses present knowledge on NAT polymorphisms, particularly in relation to individual cancer predisposition.
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PMID:Polymorphic NATs and cancer predisposition. 1049 62

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine derived from food, possibly involved in human carcinogenesis. We evaluated the formation of PhIP-DNA adducts in lymphocytes from 76 incident colorectal cancer patients likely to be exposed to dietary PhIP. To address the role of the metabolic polymorphisms relevant to PhIP-DNA adduct formation, the patients were genotyped for common polymorphisms in the N-acetyltransferase (NAT1 and NAT2), sulfotransferase (SULT1A1) and glutathione S-transferase (GSTM1 and GSTA1) genes. PhIP released from adducted DNA after hydrolysis was quantitated by liquid chromatography-tandem mass spectrometry. Overall, adducts were 3.24 +/- 3.58/10(8) nucleotides (mean +/- SD); they were not related to sex, smoking habits or age, though levels were not significantly higher in smokers, young subjects and high meat consumers. High vegetable intake significantly reduced PhIP-DNA adducts (Mann-Whitney U, p = 0.044). Individuals with the GSTM1 null genotype showed colon cancer onset at earlier age (58.8 +/- 1.8 vs. 63.5 +/- 1.6 years; Mann-Whitney U, p = 0.047). None of the genetic polymorphisms studied significantly affected PhIP-DNA adducts. However, individuals carrying 2 mutated GSTA1 alleles and younger than the median age had higher adduct levels than homozygous wild-type and heterozygous ones (Kruskal-Wallis p = 0.0008). In conclusion, these preliminary data indicate that PhIP-DNA adducts are formed in people likely to be exposed to this carcinogen through the diet, suggesting this biomarker may be useful to detect human exposure and DNA damage. Overall, the genetic polymorphisms considered had limited effect on PhIP-DNA levels, but young people with lower detoxification capacity may form a subgroup particularly susceptible to dietary carcinogen.
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PMID:Genetic polymorphisms and modulation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts in human lymphocytes. 1460 Oct 45


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