Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intact prostate epithelial cells prepared from benign prostatic hypertrophy tissues from two patients were incubated for 2 h with N-hydroxy derivatives of 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (N-OH-PhIP) or 2-amino-3,8-dimethylimidazo[4, 5-f]quinoxaline (N-OH-MeIQx). (32)P-post-labeling analysis detected PhIP and MeIQx adducts in the DNA of these cells but not in the untreated control. Adduct levels were approximately 100 times greater in N-OH-PhIP- than in N-OH-MeIQx-treated cells. Repair synthesis of DNA was observed in cells, prepared from two additional patients, treated for 24 h with these carcinogens and was greater for N-OH-PhIP than for N-OH-MeIQx. PhIP, MeIQx and their nitro derivatives did not produce repair synthesis of DNA in this system. The difference in the activity of N-OH-PhIP and N-OH-MeIQx may be due to their stability, since N-OH-MeIQx decomposed rapidly in neutral solution. Transcripts of NAT1 and NAT2 were detected by an in situ hybridization method in prostate epithelial cells, but were absent from stromal tissues. These results suggest that PhIP may be a potential carcinogen for human prostate, since cooked meats, which contain this heterocyclic amine, have been associated with human prostate cancer.
Carcinogenesis 1999 Aug
PMID:N-Acetyltransferase expression and DNA binding of N-hydroxyheterocyclic amines in human prostate epithelium. 1042 12

Among non-smokers, the factors resulting in lung carcinogenesis are poorly understood. We conducted a hospital-based case-control analysis of 294 Chinese women, of whom 217 were non-smokers, to evaluate the role of polymorphic N-acetyltransferase (NAT2) as a susceptibility factor for the disease. The proportion of slow acetylator genotypes among non-smoking cases (n = 92) and controls (n = 125) was 38.0 and 24.0%, respectively [odds ratio (OR) 2.0, 95% confidence interval (CI) 1.1-3.7]. No effect of NAT2 genotype was seen among smokers. Among non-smokers, the effect was marked for adenocarcinomas (OR 2.1, 95% CI 1.1-4.0). As NAT2 activity is known to modify risk of arylamine-induced carcinogenesis, our results suggest that exposure to arylamines in the environment may play a role in risk of lung cancer among non-smokers.
Carcinogenesis 1999 Sep
PMID:NAT2 slow acetylator genotype is associated with increased risk of lung cancer among non-smoking Chinese women in Singapore. 1046 38

Heterocyclic aromatic amines (HAs) represent a class of potent bacterial mutagens and rodent carcinogens which gain their biological activity upon metabolic conversion by phase I and phase II enzymes. Subsequent to cytochrome P450 (CYP)-dependent hydroxylation, mainly catalyzed by CYP1A2, acetylation mediated by the activity of N-acetyltransferase, NAT2, produces the ultimate electrophilic product that may react with DNA. In addition to point mutations observed in HA-exposed cells as genotoxic endpoint in vitro, loss of heterozygosity (LOH) has often been identified in HA-related rodent tumors as another endpoint in vivo. LOH may reflect a chromosomal deletion, a chromosome loss or a previous mitotic recombination event and it represents a prominent mechanism for the inactivation of tumor suppressor alleles. In this study we have investigated whether LOH observed in several HA-induced rodent tumors is related to a recombinogenic activity of HA compounds, and to address this question we have studied the genotoxic activity of several HAs in metabolically competent Saccharomyces cerevisiae strains. For this purpose expression vectors have been constructed providing simultaneous expression of three human enzymes, CYP1A2, NADPH-cytochrome P450 oxidoreductase and NAT2 in different genotoxicity tester strains. Evidence for functional expression of all three enzymes has been obtained. One strain allowed us to monitor HA-induced gene conversion, another one HA-induced chromosomal translocation. A third strain allowed us to study HA-induced forward mutations in the endogenous URA3 gene. It was found that 2-amino-3-methylimidazo-[4,5-f]quinoline and 2-amino-3, 8-dimethylimidazo-[4,5-f]quinoxaline produced a strong recombinogenic response in either recombination tester strain. The recombinogenic activity was comparable with the mutagenic activity of the compounds. The other HAs, 2-amino-3, 4-dimethyl-imidazo-[4, 5-f]quinoline, 2-amino-6-methyldipyrido-[1,2-a:3',2'-d]imidazole, 2-aminodipyrido-[1,2-a:3', 2'-d]imidazole, 3-amino-1-methyl-5H pyrido-[4,3-b]indole and 2-amino-1-methyl-6-phenyl-imidazo-[4, 5-b]pyridine, produced weak or no increases in the genotoxic endpoints of interest. The described strains may provide a suitable tool to characterize the genotoxic potential of HAs in more detail.
Carcinogenesis 1999 Nov
PMID:Heterocyclic aromatic amines efficiently induce mitotic recombination in metabolically competent Saccharomyces cerevisiae strains. 1054 18

The 'Mediterranean diet', a diet rich in cereals, fruit and vegetables, has been associated with lowering the risk of a variety of cancers of the digestive tract and the bladder. In a previous study, we showed that the high phenolic content these dietary components produce in the urine could be associated with higher antimutagenic properties of the urine and lower arylamine-DNA adducts in exfoliated bladder cells. We have conducted a case-control study on 162 bladder cancer patients and 104 hospital controls. Total aromatic DNA adducts were measured in white blood cells (WBC) of all subjects by (32)P-post-labelling. Genetically based metabolic polymorphisms were analysed by PCR-RFLP (NAT2, GSTM1, GSTT1, GSTP1, COMT and NQO1). All subjects were interviewed about their tobacco use, dietary habits and other risk factors. The odds ratio (OR) for the risk of bladder cancer according to the presence/absence of WBC DNA adducts (detection limit 0.1 RALx10(8)) was 3.7 [95% confidence interval (CI) 2.2-6.3] and a dose-response relationship with levels of adducts was apparent. The association between case/control status and the presence of WBC DNA adducts was significantly stronger in the subjects who consumed fewer portions of fruit or vegetables per day (OR 7.80, 95% CI 3.0-20.30 for 0-1 portions of vegetables) than in the heavy consumers (OR 4.98 for consumers of 2 portions daily, OR 1.97 for consumers of > or =3 portions; similar but lower estimates were found for the intake of fruit). No association was noticed between tobacco smoking and WBC DNA adducts. Only NAT-2, among the several genotypes considered, was associated in a statistically significant way with the risk of bladder cancer (OR 1.72, 95% CI 1.03-2.87) and with the levels of WBC DNA adducts. Our report suggests that fruit and vegetables could protect against bladder cancer by inhibiting the formation of DNA adducts.
Carcinogenesis 2000 Feb
PMID:White blood cell DNA adducts and fruit and vegetable consumption in bladder cancer. 1065 56

2-Amino-alpha-carboline (A alpha C) is a mutagenic and carcinogenic heterocyclic amine present in foods cooked at high temperature and in cigarette smoke. The mutagenic activity of A alpha C is dependent upon metabolic activation to N-hydroxy-A alpha C (N-OH-A alpha C); however, the metabolism of N-OH-A alpha C has not been studied. We have synthesized 2-nitro-alpha-carboline and N-OH-A alpha C and have examined in vitro bioactivation of N-OH-A alpha C by human and rodent liver cytosolic sulfotransferase(s) and acetyltransferase(s) and by recombinant human N-acetyltransferases, NAT1 and NAT2. The sulfotransferase-dependent bioactivation of N-OH-A alpha C by human liver cytosol exhibited large inter-individual variation (0.5-75, n = 14) and was significantly higher than bioactivation of N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP). Correlation and inhibition studies suggested that the isoform of sulfotransferase primarily responsible for bioactivation of N-OH-A alpha C in human liver cytosol is SULT1A1. O-Acetyltransferase-dependent bioactivation of N-OH-A alpha C by human liver cytosol also exhibited large inter-individual variation (16-192, n = 18). In contrast to other N-hydroxy heterocyclic amines, which are primarily substrates only for NAT2, both NAT1 and NAT2 catalyzed bioactivation of N-OH-A alpha C. The rate of bioactivation of N-OH-A alpha C by both NAT1 and NAT2 was significantly higher than that for N-OH-PhIP. In rat and mouse liver cytosols, the level of sulfotransferase-dependent bioactivation of N-OH-A alpha C was similar to the level in the high sulfotransferase activity human liver cytosol. The level of O-acetyltransferase-dependent bioactivation of N-OH-A alpha C in rat liver cytosol was also comparable with that in the high acetyltransferase activity human liver cytosol. However, the level of O-acetyltransferase-dependent bioactivation of N-OH-A alpha C in mouse liver cytosol was comparable with that in the low acetyltransferase activity human liver cytosol. In contrast to N-OH-PhIP, bioactivation of N-OH-A alpha C was not inhibited by glutathione S-transferase activity; however, DNA binding of N-acetoxy-A alpha C was inhibited 20% in the presence of GSH. These results suggest that bioactivation of N-OH-A alpha C may be a significant source of DNA damage in human tissues after dietary exposure to AalphaC and that the relative contribution of each pathway to bioactivation or detoxification of N-OH-A alpha C differs significantly from other N-hydroxy heterocyclic or aromatic amines.
Carcinogenesis 2000 Jul
PMID:In vitro bioactivation of N-hydroxy-2-amino-alpha-carboline. 1087 13

Epidemiological studies indicate that rapid acetylators with a high intake of well-done red meat have an increased risk of colorectal cancer. Arylamine N-acetyltransferase enzymes (E.C. 2.3.1.5) activate carcinogenic heterocyclic amines found in the crust of fried meat via O-acetylation of their N-hydroxylamines to reactive intermediates that bind covalently to DNA and produce mutations. Syrian hamsters as well as humans express two N-acetyltransferase isozymes (NAT1 and NAT2) which differ in substrate specificity and genetic control. Nucleic acid substitutions in the NAT2 gene segregate individuals into rapid, intermediate and slow acetylator phenotypes. In the present paper, we examined the role of the polymorphic NAT2 acetylator genotype in carcinogenesis induced by the food mutagens 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) or 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) by comparing Syrian hamster lines congenic at the NAT2 locus. No differences were found between rapid and slow acetylator congenic hamsters in levels of intestinal PhIP-DNA adducts. In contrast to previous studies in rats, no carcinogen-related induction of the preneoplastic lesions aberrant crypt foci or tumors was found in the intestines of rapid and slow acetylator congenic Syrian hamsters administered PhIP or IQ.
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PMID:DNA adduct levels and intestinal lesions in congenic rapid and slow acetylator syrian hamsters admi food mutagens 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) or 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). 1089 88

There is increasing evidence for the role of heterocyclic and other arylamines in carcinogenesis, including lung carcinogenesis. Chinese women have a high rate of lung cancer despite a low smoking prevalence, and studies in this population may provide useful information on risk factors other than smoking. Hepatic CYP1A2 and NAT2 are involved in the metabolism of carcinogenic arylamines, and NAT2 also catalyzes the detoxification pathway for these compounds. In this study, we examined the effect of CYP1A2 activity using a urinary caffeine metabolic ratio assay for 54 Chinese women with newly diagnosed lung cancer (including 28 adenocarcinomas) and 174 hospital controls. Among them, NAT2 genotype was available for 47 cases and 98 controls. There was no effect of CYP1A2 activity on overall risk of lung cancer in the study population [odds ratio (OR) 0.8, 95% confidence interval (CI) 0.4-1.6, adjusted for age at diagnosis, smoking and cruciferous vegetable intake]. For adenocarcinomas, the OR was 1.5, 95% CI 0.6-3.4. After further adjustment for NAT2 acetylator genotype, the OR for adenocarcinoma was 1.8 (95% CI 0.7-4.8). When the combined NAT2/CYP1A2 status was examined, women with slow NAT2 and rapid CYP1A2 activity were at highest risk (adjusted OR 6.9, 95% CI 1.3-37.6) relative to women with rapid NAT2 and slow CYP1A2 activity, for lung adenocarcinoma. While larger studies are needed to confirm or refute these results, they are consistent with a role for heterocyclic arylamines in lung carcinogenesis in this primarily non-smoking population.
Carcinogenesis 2001 Apr
PMID:Cytochrome P4501A2 (CYP1A2) activity and lung cancer risk: a preliminary study among Chinese women in Singapore. 1128 5

Breast cancer is the most frequent malignancy among women. Since genetic factors such as BRCA1 and BRCA2 as well as reproductive history constitute only 30% of the cause, environmental exposure may play a significant role in the development of breast cancer. Likewise, the relevant enzymes involved in the biotransformation of xenobiotics (from tobacco smoke, diet or other environmental sources) might play a role in breast carcinogenesis. Since individuals with modified ability to metabolize these carcinogens could have a different risk for breast cancer, we investigated the role of cytochromes P-450 (CYP1A1, CYP2D6), glutathione-S-transferases (GSTM1, GSTT1, GSTP1) and N-acetyltransferases (NAT1, NAT2) gene variants in breast carcinogenesis. A case-control study was conducted on 149 women with breast carcinoma and 207 healthy controls, both of French-Canadian origin. The CYP1A1*4 allele was found to be a significant risk determinant of breast carcinoma (OR = 3.3, 95% CI 1.1-9.7), particularly among post-menopausal women (OR = 4.0, 95% CI 1.2-13.8). The frequency of NAT2 rapid acetylators was increased among smokers (OR = 2.6, 95% CI 0.8-8.2), while the NAT1*10 allele conferred a 4-fold increase in risk among women who consumed well-done meat (OR = 4.4, 95% CI 1.0-18.9). These data suggest that CYP1A1*4, NAT1 and NAT2 variants are involved in the susceptibility to breast carcinoma by modifying the impact of exogenous and/or endogenous exposures.
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PMID:Genetic susceptibility to breast cancer in French-Canadians: role of carcinogen-metabolizing enzymes and gene-environment interactions. 1129 Oct 49

To test the hypothesis that carcinogen exposure and oxidative stress are involved in pancreatic carcinogenesis in susceptible individuals, aromatic DNA adducts and 8-hydroxyguanosine (8-OH-dG) were measured by (32)P-postlabeling and HPLC-EC, respectively, in 31 pancreatic tumors and 13 normal tissues adjacent to the tumor from patients with pancreatic cancer. Normal pancreatic tissues from 24 organ donors, from six patients with non-pancreatic cancers, and from five patients with chronic pancreatitis served as controls. It was found that tissue samples from patients with pancreatic cancer had significantly higher levels of both aromatic DNA adducts and 8-OH-dG compared with control samples. The mean (+/-S.D.) levels of aromatic DNA adducts were 101.8+/-74.6, 26.9+/-26.6, and 11.2+/-6.6 per 10(9) nucleotides in adjacent tissues, tumors, and controls, respectively. The mean (+/-S.D.) levels of 8-OH-dG were 11.9+/-9.6, 10.8+/-10.6, and 6.7+/-4.6 per 10(5) nucleotides in adjacent tissues, tumors, and controls, respectively. Polymorphisms of the CYP1A1, CYP2E1, NAT1, NAT2, GSTM1, MnSOD, and hOGG1 genes were determined in these patients. The level of aromatic DNA adducts was significantly associated with polymorphism of the CYP1A1 gene. No significant correlation was found between the level of 8-OH-dG and the MnSOD, GSTM1, and hOGG1 polymorphisms. However, one novel polymorphism/mutation of the hOGG1 gene was found in a pancreatic tumor. Mutation at codon 12 of the K-ras gene was found in 25 (81%) of 31 pancreatic tumors, including three G-to-A transitions and 22 G-to-T transversions. Patients with the G-to-T mutation had a significantly higher level of aromatic DNA adducts than those with G-to-A or wild-type codon (P=0.02). On the other hand, the K-ras mutation profile was not related to the level of 8-OH-dG. Given the limitation of sample size, these preliminary data lend further support the hypothesis that carcinogen exposure and oxidative stress are involved in pancreatic carcinogenesis.
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PMID:DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer. 1171 88

It has been hypothesized that mutational events may be involved in the atherogenetic process and that at least a portion of atherosclerotic plaques may be the results of monoclonal proliferation of a single mutated smooth muscle cell (SMC). Therefore, atherosclerosis may be similar to carcinogenesis and may have an environmental etiology. We have analyzed bulky-aromatic DNA adducts in human thoracic aortas from male subjects, aged between 30-60 years, who died suddenly or accidentally, and who had been examined by autopsy within 24 h after death. We found significantly (P < 0.001) higher DNA adduct levels in the samples from subjects with frequent atherosclerotic changes in the whole body ("Cases", N = 76) compared with those having few atherosclerotic changes ("Controls", N = 57). We also observed a significantly elevated weight of heart and plasma levels of total and LDL cholesterol in "Cases" vs "Controls". Significant differences in DNA adduct levels between smokers and nonsmokers were observed in "Controls" only. Multivariate linear regression analyses with age-adjusted data confirmed a significant influence of LDL cholesterol (P < 0.001), vitamin A (P < 0.01), smoking behavior (P < 0.05; evaluated as plasma cotinine levels) and NAT2 genotypes (P < 0.05) on bulky-aromatic DNA adduct levels. The induction of DNA adducts suggests that alterations at the DNA level may contribute to the development of atherosclerosis. Furthermore, atherogenesis and carcinogenesis may share a similar etiology, i.e. genotoxic action of environmental chemicals.
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PMID:DNA adducts and human atherosclerotic lesions. 1172 45


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