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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arylamine chemicals inflict a number of toxicities including cancer. Metabolic activation (i.e., oxidation) is required in order to elicit the toxic actions. Acetylation is an important step in the metabolic activation and deactivation of arylamines. N-acetylation forms the amide derivative which is often nontoxic. However, O-acetylation of the N-hydroxyarylamine (following oxidation) yields an acetoxy arylamine derivative which breaks down spontaneously to a highly reactive arylnitrenium ion, the ultimate metabolite responsible for mutagenic and carcinogenic lesions. Human capacity to acetylate arylamine chemicals is subject to a genetic polymorphism. Individuals segregate into rapid, intermediate, or slow acetylator phenotypes by Mendelian inheritance regulated by a single gene encoding for a polymorphic acetyltransferase isozyme (NAT2). Individuals homozygous for mutant alleles are deficient in the polymorphic acetyltransferase and are slow acetylators. A second acetyltransferase isozyme (NAT1) is monomorphic and is not regulated by the acetylator genotype. Several human epidemiological studies suggest an association between slow acetylator phenotype and urinary bladder cancer. In contrast, a few studies suggest a relationship between rapid acetylator phenotype and colorectal cancer. The basis for this paradox may relate to the relative importance of N- versus O-acetylation in the etiology of these cancers. Conclusions drawn from human epidemiological data are often compromised by uncontrolled environmental and other genetic factors. Our laboratory recently completed construction of homozygous rapid, heterozygous intermediate, and homozygous slow acetylator congenic Syrian hamsters to be homologous in greater than 99.975% of their genomes. The availability of these acetylator congenic lines should eliminate genetic variability in virtually all aspects of arylamine carcinogenesis except at the acetylator gene locus. Ongoing studies in these congenic hamster lines should provide unequivocal information regarding the role of genetic acetylator phenotype in susceptibility to arylamine-related cancers.
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PMID:Acetyltransferases and susceptibility to chemicals. 147 Nov 66

Epidemiological studies have shown that there is a significantly greater proportion of the rapid acetylator phenotype in patients with colorectal tumors than in controls; phenotype-related differences in bioactivation of dietary or environmental amines in the intestinal epithelium have been suggested as a mechanism for this effect. In the present study, we have used hepatic and intestinal cytosols to compare N-acetyltransferase (NAT1 and NAT2), O-acetyltransferase (OAT) and arylhydroxamic acid N,O-acyltransferase (AHAT) distribution in rapid and slow acetylator rabbits. The ratio (rapid/slow) for p-aminobenzoic acid acetylation (a selective substrate for NAT1) was 6 in liver, 1.7-2 in small intestine and 1.3-1.5 in large intestine while the ratio of sulfamethazine acetylation (a selective substrate for NAT2) was 150 in liver, 16-22 in small intestine and 1.8-2.5 in large intestine. The ratios (rapid/slow) for DNA binding of N-hydroxy-3,2'-dimethyl-4-aminobiphenyl and N-hydroxy-4-aminobiphenyl (primarily substrates for OAT) were 82-84 in liver, 13-20 in small intestine and 3.8-5.3 in large intestine and for DNA binding of N-hydroxy-2-acetylamidofluorene (a substrate for AHAT), the ratio was 432 in liver, 32-161 in small intestine and 8.8-13.5 in large intestine. The data show also that NAT1 activity is uniformly distributed along the intestinal tract whereas NAT2 activity is highest in the small intestine. In addition, hepatic and intestinal OAT and AHAT but not NAT1 activities in the rabbit intestine are similarly distributed to activities for NAT2, suggesting that NAT2, OAT and AHAT activities are properties of a single protein in the rapid acetylator phenotype. Moreover, OAT and AHAT activities were much higher in tissues from the rapid than the slow phenotype. The data support the hypothesis that phenotype-dependent metabolic activation of N-OH heterocyclic or aromatic amines to reactive acetoxy metabolites may be involved in the etiology of colorectal cancer.
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PMID:Distribution of acetyltransferase activities in the intestines of rapid and slow acetylator rabbits. 186 Jan 67

Exposures to carcinogens present in the diet, in cigarette smoke, or in the environment have been associated with increased risk of bladder and colorectal cancer. The aromatic amines and their metabolites, a class of carcinogen implicated in these exposures, can be N- or O-acetylated by the NAT1 and NAT2 enzymes. Acetylation may result in activation to DNA-reactive metabolites or, in some cases, detoxification. Many studies have focused on genetic variation in NAT2 and its potential as a risk factor in bladder and colorectal cancer; however, NAT1 activity is higher in bladder and colonic mucosa than NAT2, and the NAT1 enzyme also exhibits phenotypic variation among human tissue samples. We hypothesized that specific genetic variants in the polyadenylation signal of the NAT1 gene would alter tissue levels of NAT1 enzyme activity and used a PCR-based method to distinguish polymorphic NAT1 alleles in samples obtained from 45 individuals. When the NAT1 genotype was compared with the NAT1 phenotype in bladder and colon tissue samples (p-aminobenzoic acid activity), we observed a approximately 2-fold higher NAT1 enzyme activity in samples from individuals who inherited a variant polyadenylation signal (NAT1*10 allele). This is the first observation relating a genetic polymorphism in NAT1 to a rapid/slow NAT1 phenotype in humans.
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PMID:Polymorphism in the N-acetyltransferase 1 (NAT1) polyadenylation signal: association of NAT1*10 allele with higher N-acetylation activity in bladder and colon tissue. 758 80

Exposure to carcinogens present in the diet, cigarette smoke, or the environment may be associated with increased risk of colorectal cancer. Aromatic amines (aryl- and heterocyclic) are a class of carcinogens that are important in these exposures. These compounds can be N- or O-acetylated by the NAT1 or NAT2 enzymes, resulting in activation or in some cases detoxification. Recent studies have shown that both NAT2 and NAT1 genes exhibit variation in human populations and that rapid acetylation by the NAT2 enzyme may be a risk factor for colorectal cancer. In this study we have analyzed for genetic polymorphism in both NAT1 and NAT2 in a group of 202 colorectal cancer patients and 112 control subjects from Staffordshire, England. We find significantly increased risk (odds ratio, 1.9; 95% confidence interval, 1.2-3.2; P = 0.009) associated with the NAT1*10 allele of NAT1, an allele that contains a variant polyadenylation signal. Individuals with higher stage tumors (Duke's C) were more likely to inherit this variant allele (odds ratio, 2.5; 95% confidence interval, 1.3-4.7; P = 0.005). In contrast, rapid acetylation genotypes of NAT2 were not a significant risk factor in this English population. However, we found that the risk associated with the NAT1 variant allele (NAT1*10) was most apparent among NAT2 rapid acetylators (odds ratio, 2.8; 95% confidence interval, 1.4-5.7; P = 0.003), suggesting a possible gene-gene interaction between NAT1 and NAT2 (test for interaction; P = 0.12). This is the first study to test for cancer risk associated with the NAT1 gene, and these positive findings suggest that NAT1 alleles may be important genetic determinents of colorectal cancer risk.
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PMID:Polyadenylation polymorphism in the acetyltransferase 1 gene (NAT1) increases risk of colorectal cancer. 762 61

Polymorphic expression of arylamine N-acetyltransferase (EC 2.3.1.5) may be a differential risk factor in metabolic activation of arylamine carcinogens and susceptibility to cancers related to arylamine exposures. Human epidemiological studies suggest that rapid acetylator phenotype may be associated with higher incidences of colorectal cancer. We used restriction fragment length polymorphism analysis to determine acetylator genotypes of 44 subjects with colorectal cancer and 28 non-cancer subjects of similar ethnic background (i.e., approximately 25% Black and 75% White). The polymorphic N-acetyltransferase gene (NAT2) was amplified by the polymerase chain reaction from DNA templates derived from human colons of colorectal and non-cancer subjects. No significant differences in NAT2 allelic frequencies (i.e., WT, M1, M2, M3 alleles) or in acetylator genotypes were found between the colorectal cancer and non-cancer groups. No significant differences in NAT2 allelic frequencies were observed between Whites and Blacks or between males and females. Cytosolic preparations from the human colons were tested for expression of arylamine N-acetyltransferase activity. Although N-acetyltransferase activity was expressed for each of the arylamines tested (i. e., p-aminobenzoic acid, 4-aminobiphenyl, 2-aminofluorene, beta-naphthylamine), no correlation was observed between acetylator genotype and expression of human colon arylamine N-acetyltransferase activity. Similarly, no correlation was observed between subject age and expression of human colon arylamine N-acetyltransferase activity. These results suggest that arylamine N-acetyltransferase activity expressed in human colon is catalyzed predominantly by NAT1, an arylamine N-acetyltransferase that is not regulated by NAT2 acetylator genotype.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human acetylator genotype: relationship to colorectal cancer incidence and arylamine N-acetyltransferase expression in colon cytosol. 790 79

Acetylator genotype is regulated at the polymorphic acetyltransferase (NAT2) gene locus in humans and other mammals such as Syrian hamsters. Human slow acetylator phenotypes have been associated with increased incidences of urinary bladder cancers, whereas rapid acetylators have been associated with increased incidences of colorectal cancers. The genetic predisposition of rapid acetylators to colorectal cancers suggests localized metabolic activation of arylamine carcinogen metabolites by polymorphic N-acetyltransferase (NAT2) in colon tissues. We tested this hypothesis in Bio. 82.73/H Syrian hamster lines which are congenic at the NAT2 gene locus. Congenic Bio. 82.73/H Syrian hamsters expressed acetylator genotype-dependent N-acetyltransferase activity in colon cytosols toward arylamine carcinogens such as 2-aminofluorene and 4-aminobiphenyl. Partial purification of the hamster colon cytosol by anion exchange chromatography identified two N-acetyltransferase isozymes analogous to those previously described in liver and urinary bladder. One of the isozymes (NAT2) exhibited acetylator genotype-dependent expression for the N-acetylation of each arylamine tested: p-aminophenol; 2-aminofluorene; 4-aminobiphenyl; 3,2'-dimethyl-4-aminobiphenyl; and 2-amino-dipyrido[1,2-a:3',2'd]imidazole as well as for the metabolic activation (via O-acetylation) of N-hydroxy-2-aminofluorene to form DNA adducts. Although NAT2 catalyzed the metabolic activation of N-hydroxy-2-acetyl-aminofluorene to DNA adducts, the rates were lower, were paraoxon-sensitive, and did not reflect acetylator genotype. A second isozyme (NAT1) also catalyzed the N-acetylation of each arylamine as well as the metabolic activation of N-hydroxy-2-aminofluorene and N-hydroxy-2-acetylaminofluorene to DNA adducts at rates that were independent of acetylator genotype. Metabolic activation of N-hydroxy-2-aminofluorene catalyzed by both NAT1 and NAT2 was resistant to 100 microM paraoxon, an inhibitor of microsomal deacetylases. Metabolic activation of N-hydroxy-2-acetylaminofluorene by NAT1 and NAT2 was partially sensitive to 100 microM paraoxon. Michaelis-Menten kinetic constants were determined for the colon NAT1 and NAT2 isozymes and compared to previous determinations for liver NAT1 and NAT2. For each of the arylamines tested, both apparent Km and apparent Vmax were higher for NAT2 than NAT1. In rapid acetylator hamster colon, NAT2/NAT1 activity ratios were 18 and 13 for the N-acetylation of 2-aminofluorene and 4-aminobiphenyl and 28 for the O-acetylation of N-hydroxy-2-aminofluorene. These results strongly support the role of the polymorphic NAT2 gene locus in the local metabolic activation of N-hydroxyarylamine carcinogens in colon and provide mechanistic support for human epidemiological studies suggesting a predisposition of rapid acetylators to colorectal cancer.
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PMID:Metabolic activation of N-hydroxy-2-aminofluorene and N-hydroxy-2-acetylaminofluorene by monomorphic N-acetyltransferase (NAT1) and polymorphic N-acetyltransferase (NAT2) in colon cytosols of Syrian hamsters congenic at the NAT2 locus. 842 84

Carcinogen-DNA adducts are generally regarded as relevant biomarkers of carcinogen exposure and their levels in target tissues have often been predictive of tumor incidence in experimental animals. Thus, human risk assessment procedures have utilized dose-response models that assume proportional relationships between carcinogen exposure and cancer susceptibility, even though wide inter-individual variations in human metabolic activating enzymes have now been clearly established. To evaluate these approaches, we have examined the relationship between carcinogen exposure, DNA adduct levels, metabolic activation phenotypes, and cancers of the larynx, urinary bladder, and colon. Cigarette smoking is a strong risk factor for cancers of the larynx and urinary bladder. In the larynx, the DNA adducts appear to be derived predominantly from polycyclic aromatic hydrocarbons (PAHs) and are evident only in tissue from smokers. However, adduct levels appear to be determined primarily by expression of cytochrome P450 (CYP) 2C9/10, which varies > 10-fold in different individuals. This CYP catalyzes the metabolic activation of benzo (alpha) pyrene (BP) to a 9-hydroxy-BP-DNA adduct that accounts for up to 25% of the putative PAH adducts formed in vivo. For the urinary bladder, putative aromatic amine (AA)-DNA adducts are predominant and are significantly elevated in current smokers. Rapid CYP1A2 and slow acetyltransferase (NAT2) phenotypes have been previously implicated in the activation (N-oxidation) and detoxification (N-acetylation) of AAs for human bladder carcinogenesis. Data now indicate that NAT1, which is expressed in human urothelium and catalyzes the O-acetylation of N-hydroxy arylamines, is significantly correlated with DNA adduct levels and is bimodally distributed in this tissue. Colo-rectal cancer risk, which has been associated with exposure to heterocyclic amines (HAs) in cooked foods, is strongly elevated in individuals with the combined rapid phenotypes for CYP1A2 and NAT2. These enzymes are uniquely responsible for HA N-oxidation and subsequent O-acetylation, forming DNA adducts that are found in human colon. These studies indicate that cancer risk assessment procedures should be redesigned to include biomarkers of susceptibility, especially those involved in carcinogen bioactivation.
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PMID:Cytochrome P-450 and acetyltransferase expression as biomarkers of carcinogen-DNA adduct levels and human cancer susceptibility. 889 86

Increased cancer risk has been associated with functional polymorphisms that occur within the genes coding for the N-acetyltransferase enzymes NAT1 and NAT2. We detected two NAT1 polymorphisms in colorectal cancer patients by heteroduplex analysis. DNA sequencing revealed the wild-type sequence (NAT1*4) and two single base substitutions at adjacent positions 999 bp (C to T, NAT1*14) and 1000 bp (G to A, NAT1*15) of the gene, changing Arg187 to a stop codon and Arg187 to Gln respectively. NAT1 alleles NAT1*4 (0.98) and NAT1*15 (0.02) were present at a similar frequency in patients with colorectal cancer (n=260) and in a Scottish control group (n=323). The third allele, NAT1*14, was present only in the colorectal cancer group at a frequency of 0.006. NAT1 genotype NAT1*4/ NAT1*15 was significantly less frequent in individuals that had a slow NAT2 genotype. This was observed in both cancer and control groups and suggests that this association was unrelated to cancer risk. We conclude that polymorphisms within the coding region of the NAT1 gene are infrequent and do not appear to have an independent association with colorectal cancer risk. However, the relationship between NAT1 and NAT2 polymorphisms appears non-random, suggesting a linkage between these enzymes.
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PMID:N-acetyl transferase 1: two polymorphisms in coding sequence identified in colorectal cancer patients. 952 34

N-acetyltransferase NAT1, together with enzymes CYP1A2 and NAT2, helps convert heterocyclic amines to mutagens. Epidemiologic studies of the association of variants of these enzymes with colorectal cancer may provide indirect support for a heterocyclic amine mechanism. We used single strand conformation polymorphism and heteroduplex analysis to screen fro mutations in the NAT1 coding region in a case-control study (n = 932) of colorectal adenomas, which are precursors to cancer. Thirteen different single-base mutations were found: C97T, C190T, T402C, G445A-G459A-T640G ( a combination of three mutations), C559T, G560A, A613G, A752T, T777C, G781A, and A787G. Function of novel mutations was tested by bacterial production of enzymes and measurements of Km, Vmax, and stability. However, on 24-control individuals and 18 cases carried an inactivating NAT1 mutation. When combined with our data on the NAT2 acetylation polymorphism, we saw no evidence for an association between N-acetyltransferases and prevalence of adenomas. Larger sample sizes are required for further evaluation.
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PMID:Variants of N-acetyltransferase NAT1 and a case-control study of colorectal adenomas. 968 72

Carcinogenic heterocyclic amines are activated by N-acetyltransferase (NAT) enzymes, encoded by NAT1 and NAT2, to genotoxic compounds that can form DNA adducts in the colon epithelium. We have examined the relation of polymorphisms in the genes coding for both enzymes to risk of colorectal cancer and the gene-environment interaction with red meat intake among participants in the prospective Physicians' Health Study. Baseline blood samples from 212 men subsequently diagnosed with colorectal cancer during 13 years of follow-up were genotyped, along with 221 controls. NAT genotypes were analyzed by a PCR-restriction fragment length polymorphism method. Effect modification of the relation of red meat intake and risk of colorectal cancer by NAT genotype was assessed using conditional logistic regression. There was no overall independent association of NAT acetylation genotypes and colorectal cancer risk. The relative risks for the rapid acetylation genotype were 0.93 [95% confidence interval (CI), 0.61-1.42] for NAT1, 0.80 (95% CI, 0.53-1.19) for NAT2, and 0.81 (95% CI, 0.52-1.27) for NAT1/NAT2 combined. We observed a stronger association of red meat intake with cancer risk among NAT rapid acetylators, especially among men 60 years old or older. Among those men who were rapid acetylators for both NAT1 and NAT2, consumption of >1 serving of red meat per day was associated with a relative risk of 5.82 (95% CI, 1.11-30.6) compared with consumption of < or = 0.5 serving per day (P, trend = 0.02). These prospective data, which need to be confirmed in other studies, suggest that polymorphisms in the NAT genes confer differential susceptibility to the effect of red meat consumption on colorectal cancer risk.
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PMID:A prospective study of N-acetyltransferase genotype, red meat intake, and risk of colorectal cancer. 969 60


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