Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005684 (bladder cancer)
 16,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

4-Aminobiphenyl (4-ABP) is a human and mouse bladder carcinogen. Epidemiological studies have shown that individuals with a slow acetylator phenotype, especially those exposed to high levels of carcinogenic aromatic amines, show an increased susceptibility to bladder cancer. In order to determine if a slow acetylator phenotype results in increased DNA damage, congenic mouse strains C57BL/6J and B6.A-Nat(s), which differ genetically at the acetyltransferase (EC 2.3.1.5) locus as homozygous rapid (Natr/Natr) and homozygous slow (Nat(s)/Nat(s)) acetylators respectively, were continuously administered 4-ABP.HCl (55-300 p.p.m.) in their drinking water for 28 days. The levels of covalently bound N-(deoxyguanosin-8-yl)-4-ABP-DNA adducts, which are believed to be critical for the initiation of tumors, were quantitated in the liver and bladder by 32P-postlabeling analysis. The levels of the hepatic DNA adduct increased with dose in both sexes, but were independent of the mouse acetylator genotype. At comparable doses, however, the levels of DNA adducts were 2-fold higher in the liver of the female as compared to the male animals. The DNA adducts also increased with dose in bladder of the male mice, but in contrast to the liver, the adduct levels were approximately 2-fold lower in the bladder DNA of the female mice. Also in contrast to the liver, the levels of bladder DNA adducts were significantly higher (P < or = 0.03) in the phenotypic rapid acetylator females compared to the slow acetylators at both 75 and 150 p.p.m. doses; the median levels of adducts were 10-20% higher in the phenotypic slow acetylator male bladders compared to their rapid acetylator counterparts. The results of these studies are consistent with the increased carcinogenicity of 4-ABP to the liver of female mice and the bladder of male mice. They further suggest that factors other than acetylator phenotype limit the extent of DNA adduct formation from 4-ABP in these mice.
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PMID:DNA adduct levels in congenic rapid and slow acetylator mouse strains following chronic administration of 4-aminobiphenyl. 142 49

Epidemiological studies have suggested that genetically based polymorphism for N-acetylation of arylamines might play an important role in the susceptibility to bladder cancer induction. However, these studies show large differences in the extent of such susceptibility. We have undertaken collaborative investigations (with IARC, MIT, NCI and NCTR) which couple internal dosimetry among smokers (measurement of hemoglobin and DNA adducts of arylamines) with the assessment of metabolic polymorphism. In one of these studies, hemoglobin adducts of 14 arylamines (including 2-naphthylamine and 4-aminobiphenyl) were analysed in a group of 86 subjects (smokers and non-smokers) in order to establish whether the inter-individual variability left unexplained by tobacco smoking could be attributed to differences in individual metabolic patterns. In another investigation on 100 smokers and non-smokers, metabolic polymorphism for N-acetylatransferase was assessed by measuring five different urinary metabolites of caffeine, after timed urine collection following coffee consumption. Arylamine-hemoglobin adducts were also measured. 4-Aminobiphenyl-hemoglobin adducts were found to be related to both the quantity and the type of tobacco smoked, as well as to the acetylator phenotype (independently of smoking habits).
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PMID:The use of biomarkers in epidemiology: the example of bladder cancer. 147 Nov 98

Hemoglobin adducts of 15 aromatic amines were determined in nonsmokers and smokers of blond- or black-tobacco cigarettes living in Turin, Italy. The subjects were all males age 55 or less and were representative of the population previously examined in a case/control study of bladder cancer. 4-Aminobiphenyl adduct levels were found to be significantly different in the three groups, and the differences were approximately proportional to the relative risk of each group. Adjustment for age and cigarette consumption did not materially influence the differences. A significant correlation of adduct levels with cigarette consumption was also observed for all smokers as well as for smokers of blond tobacco. Other amines for which significant differences between smokers and nonsmokers were observed were 3-aminobiphenyl, 2-naphthylamine, o- and p-toluidine, 2,4-dimethylaniline, and 2-ethylaniline. Some of these amines are human bladder carcinogens, and their occurrence in blood as hemoglobin adducts is evidence for their metabolic activation. Thus, by a combination of traditional epidemiological methods and modern chemical analyses, we have provided evidence for a biochemical basis for the often observed association between cigarette smoking and bladder cancer.
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PMID:Hemoglobin adducts of aromatic amines: associations with smoking status and type of tobacco. 320 Aug 58

Epidemiologic studies have suggested that smokers of air-cured tobacco (rich in arylamines) are at higher risk of bladder cancer than smokers of flue-cured tobacco. The risk has been shown to be modulated by the N-acetyltransferase genotype. We analyzed the biopsies of 45 patients with bladder cancer. p53 mutations were sought by direct sequencing, and 4-aminobiphenyl-DNA adducts were measured by negative ion gas chromatography-mass spectrometry. 4-Aminobiphenyl-DNA adducts were higher in smokers of air-cured tobacco and in current smokers, but no relationship with the number of cigarettes smoked was found. Adducts were higher in more advanced histologic grades of tumors. No pattern was evident for p53 mutations. Seven of 9 mutations occurred in grade 3 tumors. No association was found between 4-ABP adducts and GSTM1 or NAT2 genetic polymorphisms.
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PMID:4-Aminobiphenyl-DNA adducts and p53 mutations in bladder cancer. 946 49

4-Aminobiphenyl (4-ABP), a potent carcinogen in rodents (liver cancer) and human (bladder cancer), is found as an environmental contaminant and in tobacco smoke. Hemoglobin adducts and lung DNA adducts of 4-ABP are found in tobacco smokers. In vitro metabolism studies with human and rat liver microsomes have shown that CYP1A2 is primarily responsible for catalyzing N-hydroxylation, the initial step in the metabolic activation of 4-ABP. To determine whether this P450 is a rate limiting pathway for hepatocarcinogenesis, CYP1A2-null mice were analyzed at 16 months of age and were compared with wild-type mice in their response to 4-ABP using the neonatal mouse bioassay and two different doses of the carcinogen. Overall differences in incidences of hepatocellular adenoma, carcinoma and preneoplastic foci were not significant between either genotypes or 4-ABP doses used, whereas small, but significant, differences were found for specific types of foci. These results suggest that while CYP1A2 levels may not be rate limiting for 4-ABP metabolism to produce tumors and foci, it may modulate the induction process of some types of liver foci in either a positive or negative manner. In vitro studies using CYP1A2-null and wild-type mouse liver microsomes revealed that CYP1A2 is not the sole P450 required for 4-ABP N-hydroxylation and that another, yet to be identified, P450 is likely to be involved.
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PMID:CYP1A2 is not the primary enzyme responsible for 4-aminobiphenyl-induced hepatocarcinogenesis in mice. 1046 30

4-Aminobiphenyl (4-ABP) is a major etiological agent for human bladder cancer. Metabolically activated 4-ABP is able to interact with DNA to form adducts that may induce mutations and initiate carcinogenesis. Thirty to sixty percent of bladder cancer has a mutation in the tumor suppressor p53 gene, and the mutational spectrum bears unique features. To date the DNA binding spectrum of 4-ABP in the p53 gene is not known due to the lack of methodology to detect 4-ABP-DNA adducts at nucleotide sequence level. We have found that UvrABC nuclease, a nucleotide excision repair complex isolated from Escherichia coli, is able to incise specifically and quantitatively DNA fragments modified with N-hydroxy-4-aminobiphenyl (N-OH-4-ABP), an activated intermediate of 4-ABP. Using the UvrABC nuclease incision method, we mapped the binding spectrum of N-OH-4-ABP in DNA fragments containing exons 5, 7, and 8 of the human p53 gene and also determined the effect of C5 cytosine methylation on N-OH-4-ABP-DNA binding. We found that codon 285, a mutational hotspot at a non-CpG site in bladder cancer, is the preferential binding site for N-OH-4-ABP. We also found that C5 cytosine methylation greatly enhanced N-OH-4-ABP binding at CpG sites, and that two mutational hotspots at CpG sites, codons 175 and 248, became preferential binding sites for N-OH-4-ABP only after being methylated. These results suggest that both the unique DNA binding specificity of 4-ABP and cytosine methylation contribute to the mutational spectrum of the p53 gene in human bladder cancer.
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PMID:N-hydroxy-4-aminobiphenyl-DNA binding in human p53 gene: sequence preference and the effect of C5 cytosine methylation. 1200 4

4-Aminobiphenyl (4-ABP) is an arylamine that has long been associated with human and animal urinary bladder cancer. N-glucuronidation is an important metabolic pathway that contributes significantly to 4-ABP-bladder carcinogenesis by facilitating transport of the active metabolites from the liver to the bladder. This pathway is carried out by UDP-glucuronosyltransferase (UGTs). These enzymes are located in the inner membrane of the endoplasmic reticulum. Full UGT activity is not achieved until membrane constraints are removed. This study was conducted to optimize the incubation conditions of 4-ABP N-glucuronidation. The kinetic parameters of the isozymes most commonly involved in arylamine glucuronidation, namely UGT1A4 and UGT1A9, were also determined. The UGT reaction was linear in the incubation time (0-90 min) and in the microsomal protein range of 0-0.5 mg. Alamethicin, a pore-forming agent, was found to be the best reagent to activate UGTs. It increased the enzyme activity by nearly 8-fold and this activation was at concentration of 50 microg mg(-1) protein. Interestingly, UGT1A4 glucuronidated 4-ABP with more affinity and efficiency than did UGT1A9. The K(m) and V(max) of UGT1A4 for 4-ABP were 58.8 microm and 234.9 pmol min(-1) mg(-1) protein, respectively, and 227.5 microm and 31.2 pmol min(-1) mg(-1) protein for UGT1A9. Furthermore, hecogenin was found to be a competitive inhibitor for UGT1A4. It increased the K(m) of UGT1A4 for 4-ABP by nearly 10 fold at a concentration of 50 microm. This is the first report that tried to optimize the incubation conditions for 4-ABP N-glucuronidation and characterized the enzyme kinetic parameters of UGT isoforms catalysing 4-ABP N-glucuronidation.
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PMID:4-Aminobiphenyl N-glucuronidation by liver microsomes: optimization of the reaction conditions and characterization of the UDP-glucuronosyltransferase isoforms. 1708 Apr 1

Bladder cancer risk is significantly higher in men than in women. 4-Aminobiphenyl (ABP) is a major human bladder carcinogen from tobacco smoke and other sources. In mice, male bladder is more susceptible to ABP-induced carcinogenesis than female bladder, but ABP is more carcinogenic in the livers of female mice than of male mice. Here, we show that castration causes male mice to acquire female phenotype regarding susceptibility of bladder and liver to ABP. However, spaying has little impact on organ susceptibility to ABP. Liver UDP-glucuronosyltransferases (UGTs) are believed to protect liver against but sensitize bladder to ABP, as glucuronidation of ABP and its metabolites generally reduces their toxicity and promotes their elimination via urine, but the metabolites are labile in urine, delivering carcinogenic species to the bladder. Indeed, liver expression of ABP-metabolizing human UGT1A3 transgene in mice increases bladder susceptibility to ABP. However, ABP-specific liver UGT activity is significantly higher in wild-type female mice than in their male counterparts, and castration also significantly increases ABP-specific UGT activity in the liver. Taken together, our data suggest that androgen increases bladder susceptibility to ABP via liver, likely by modulating an ABP-metabolizing liver enzyme, but exclude UGT as an important mediator.
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PMID:The inverse relationship between bladder and liver in 4-aminobiphenyl-induced DNA damage. 2559 34