4-Aminobiphenyl and DNA Reactivity: Case Study Within the Context of the 2006 IPCS Human Relevance Framework for Analysis of a Cancer Mode of Action for Humans

The IPCS Human Relevance Framework was evaluated for a DNA-reactive (genotoxic) carcinogen, 4-aminobiphenyl, based on a wealth of data in animals and humans. The mode of action involves metabolic activation by N-hydroxylation, followed by N-esterification leading to the formation of a reactive electrophile, which binds covalently to DNA, principally to deoxyguanosine, leading to an increased rate of DNA mutations and ultimately to the development of cancer. In humans and dogs, the urinary bladder urothelium is the target organ, whereas in mice it is the bladder and liver; in other species, other tissues can be involved. Differences in organ specificity are thought to be due to differences in metabolic activation versus inactivation. Based on qualitative and quantitative considerations, the mode of action is possible in humans. Other biological processes, such as toxicity and regenerative proliferation, can significantly influence the dose response of 4-aminobiphenyl-induced tumors. Based on the IPCS Human Relevance Framework, 4-aminobiphenyl would be predicted to be a carcinogen in humans, and this is corroborated by extensive epidemiologic evidence. The IPCA Human Relevance Framework is useful in evaluating DNA-reactive carcinogens.

[1]  H. Wolf,et al.  N-acetyltransferase phenotype and risk in urinary bladder cancer: approaches in molecular epidemiology. Preliminary results in Sweden and Denmark. Environmental Health Perspectives;1979:71-79. , 2007, International journal of epidemiology.

[2]  F. Beland,et al.  Levels of 4‐aminobiphenyl‐induced somatic H‐ras mutation in mouse liver DNA correlate with potential for liver tumor development , 2005, Molecular carcinogenesis.

[3]  Y. Oda.  Analysis of the involvement of human N-acetyltransferase 1 in the genotoxic activation of bladder carcinogenic arylamines using a SOS/umu assay system. , 2004, Mutation research.

[4]  Jack A. Taylor,et al.  p53 mutations in bladder cancer: evidence for exogenous versus endogenous risk factors. , 2003, Cancer research.

[5]  Mario Medvedovic,et al.  4-aminobiphenyl-induced liver and urinary bladder DNA adduct formation in Cyp1a2(-/-) and Cyp1a2(+/+) mice. , 2003, Journal of the National Cancer Institute.

[6]  R. Erickson,et al.  The effects of genetic variation in N-acetyltransferases on 4-aminobiphenyl genotoxicity in mouse liver. , 2003, Chemico-biological interactions.

[7]  S. Tannenbaum,et al.  Nonsmoking-related arylamine exposure and bladder cancer risk. , 2003, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[8]  A. Neugut,et al.  Evaluation of 4-aminobiphenyl-DNA adducts in human breast cancer: the influence of tobacco smoke. , 2003, Carcinogenesis.

[9]  G. Pfeifer,et al.  Mutational signature of the proximate bladder carcinogen N-hydroxy-4-acetylaminobiphenyl: inconsistency with the p53 mutational spectrum in bladder cancer. , 2002, Cancer research.

[10]  Xin Lu,et al.  Live or let die: the cell's response to p53 , 2002, Nature Reviews Cancer.

[11]  S. J. Culp,et al.  Occurrence of H-ras codon 61 CAA to AAA mutation during mouse liver tumor progression. , 2002, Carcinogenesis.

[12]  W. Rom,et al.  N-hydroxy-4-aminobiphenyl-DNA binding in human p53 gene: sequence preference and the effect of C5 cytosine methylation. , 2002, Biochemistry.

[13]  K. Helin,et al.  The role of p53 and pRB in apoptosis and cancer. , 2002, Current opinion in genetics & development.

[14]  D. Grignon,et al.  Structural alteration of p53 protein in patients with muscle invasive bladder transitional cell carcinoma. , 2001, The Journal of urology.

[15]  M Younes,et al.  IPCS conceptual framework for evaluating a mode of action for chemical carcinogenesis. , 2001, Regulatory toxicology and pharmacology : RTP.

[16]  J. Brockmöller,et al.  Association of NAT1 and NAT2 polymorphisms to urinary bladder cancer: significantly reduced risk in subjects with NAT1*10. , 2001, Cancer research.

[17]  S R Tannenbaum,et al.  Gender- and smoking-related bladder cancer risk. , 2001, Journal of the National Cancer Institute.

[18]  H. von der Maase,et al.  Allelic deletions of cell growth regulators during progression of bladder cancer. , 2000, Cancer research.

[19]  A. Charchanti,et al.  Immunohistochemical expression of retinoblastoma gene product (Rb), p53 protein, MDM2, c-erbB-2, HLA-DR and proliferation indices in human urinary bladder carcinoma. , 2000, Histology and histopathology.

[20]  J. Ward,et al.  CYP1A2 is not the primary enzyme responsible for 4-aminobiphenyl-induced hepatocarcinogenesis in mice. , 1999, Carcinogenesis.

[21]  C. Mcqueen,et al.  Mutagenicity of 4-aminobiphenyl and 4-acetylaminobiphenyl in Salmonella typhimurium strains expressing different levels of N-acetyltransferase. , 1999, Toxicology and applied pharmacology.

[22]  M. Churchwell,et al.  Quantitative analysis of 4-aminobiphenyl-C8-deoxyguanosyl DNA adducts produced in vitro and in vivo using HPLC-ES-MS. , 1999, Carcinogenesis.

[23]  J. Ashby,et al.  Mutagenicity of the human bladder carcinogen 4-aminobiphenyl to the bladder of MutaMouse transgenic mice. , 1998, Mutation research.

[24]  P. Vineis,et al.  4‐aminobiphenyl‐DNA adducts and p53 mutations in bladder cancer , 1998, International journal of cancer.

[25]  G. Curigliano,et al.  4-Aminobiphenyl-DNA adducts in laryngeal tissue and smoking habits: an immunohistochemical study. , 1998, Carcinogenesis.

[26]  J. Essigmann,et al.  Specificity of mutagenesis by 4-aminobiphenyl: mutations at G residues in bacteriophage M13 DNA and G-->C transversions at a unique dG(8-ABP) lesion in single-stranded DNA. , 1997, Carcinogenesis.

[27]  D. Warshawsky,et al.  Chronic, topical administration of 4-aminobiphenyl induces tissue-specific DNA adducts in mice. , 1997, Toxicology and applied pharmacology.

[28]  C. Cordon-Cardo,et al.  Alterations of tumor suppressor genes in bladder cancer. , 1997, Seminars in diagnostic pathology.

[29]  M. Doll,et al.  Cloning, sequencing, and recombinant expression of NAT1, NAT2, and NAT3 derived from the C3H/HeJ (rapid) and A/HeJ (slow) acetylator inbred mouse: functional characterization of the activation and deactivation of aromatic amine carcinogens. , 1997, Toxicology and applied pharmacology.

[30]  P. Fu,et al.  Inhibitory effect of caloric restriction on tumorigenicity induced by 4-aminobiphenyl and 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) in the CD1 newborn mouse bioassay. , 1996, Cancer letters.

[31]  G. Curigliano,et al.  Immunohistochemical quantitation of 4-aminobiphenyl-DNA adducts and p53 nuclear overexpression in T1 bladder cancer of smokers and nonsmokers. , 1996, Carcinogenesis.

[32]  M. Manjanatha,et al.  H- and K-ras mutational profiles in chemically induced liver tumors from B6C3F1 and CD-1 mice. , 1996, Journal of toxicology and environmental health.

[33]  F. Beland,et al.  DNA adduct formation and tumorigenesis in mice during the chronic administration of 4-aminobiphenyl at multiple dose levels. , 1995, Carcinogenesis.

[34]  E. Gallagher,et al.  Role of cytochrome P4501A2 in chemical carcinogenesis: implications for human variability in expression and enzyme activity. , 1995, Pharmacogenetics.

[35]  S. Cohen,et al.  Role of urinary physiology and chemistry in bladder carcinogenesis. , 1995, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[36]  R. Santella,et al.  Quantitative immunohistochemical analysis of 4-aminobiphenyl-DNA in cultured cells and mice: comparison to gas chromatography/mass spectroscopy analysis. , 1995, Chemical research in toxicology.

[37]  S. Swaminathan,et al.  Detection of deoxyadenosine-4-aminobiphenyl adduct in DNA of human uroepithelial cells treated with N-hydroxy-4-aminobiphenyl following nuclease P1 enrichment and 32P-postlabeling analysis. , 1995, Carcinogenesis.

[38]  D. Neal,et al.  Expression of retinoblastoma gene product and p53 protein in bladder carcinoma: correlation with Ki67 index. , 1995, British journal of urology.

[39]  F. Kadlubar,et al.  Metabolic activation of the N-hydroxy derivative of the carcinogen 4-aminobiphenyl by human tissue sulfotransferases. , 1995, Carcinogenesis.

[40]  T. Sun,et al.  Mammalian uroplakins. A group of highly conserved urothelial differentiation-related membrane proteins. , 1994, The Journal of biological chemistry.

[41]  S. Swaminathan,et al.  Mutagenic activation of 4-aminobiphenyl and its N-hydroxy derivatives by microsomes from cultured human uroepithelial cells. , 1993, Mutagenesis.

[42]  F. Beland,et al.  DNA adduct measurements and tumor incidence during chronic carcinogen exposure in animal models: implications for DNA adduct-based human cancer risk assessment. , 1992, Chemical research in toxicology.

[43]  S. Swaminathan,et al.  Microsome-mediated transacetylation and binding of N-hydroxy-4-aminobiphenyl to nucleic acids by hepatic and bladder tissues from dog. , 1992, Carcinogenesis.

[44]  L. Couch,et al.  DNA adduct levels in congenic rapid and slow acetylator mouse strains following chronic administration of 4-aminobiphenyl. , 1992, Carcinogenesis.

[45]  A. Sahin,et al.  Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer. , 1992, Journal of the National Cancer Institute.

[46]  S. Swaminathan,et al.  Metabolism and nucleic acid binding of N-hydroxy-4-acetylaminobiphenyl and N-acetoxy-4-acetylaminobiphenyl by cultured human uroepithelial cells. , 1992, Cancer research.

[47]  S. M. Frederickson,et al.  Acetyl transferase-mediated metabolic activation of N-hydroxy-4-aminobiphenyl by human uroepithelial cells. , 1992, Carcinogenesis.

[48]  T. Eling,et al.  The oxidation of 4-aminobiphenyl by horseradish peroxidase. , 1992, Chemical research in toxicology.

[49]  M. Lindstrom,et al.  Tumorigenic transformation and neoplastic progression of human uroepithelial cells after exposure in vitro to 4-aminobiphenyl or its metabolites. , 1992, Cancer research.

[50]  M. Lindstrom,et al.  Induction of thioguanine-resistant mutations in human uroepithelial cells by 4-aminobiphenyl and its N-hydroxy derivatives. , 1992, Cancer research.

[51]  P. Fu,et al.  Comparative carcinogenicity of 4-aminobiphenyl and the food pyrolysates, Glu-P-1, IQ, PhIP, and MeIQx in the neonatal B6C3F1 male mouse. , 1992, Cancer letters.

[52]  A. delle Rose,et al.  Levels of the adducts of 4-aminobiphenyl to hemoglobin in control subjects and bladder carcinoma patients. , 1991, Cancer letters.

[53]  M. Knowles,et al.  Loss of heterozygosity at the RB locus is frequent and correlates with muscle invasion in bladder carcinoma. , 1991, Oncogene.

[54]  S. Maeda,et al.  Inactivation of the retinoblastoma gene in human bladder and renal cell carcinomas. , 1991, Cancer research.

[55]  C. Cordon-Cardo,et al.  Molecular genetic alterations in superficial and locally advanced human bladder cancer. , 1991, Cancer research.

[56]  R. Hoover,et al.  Measurement of 4-aminobiphenyl-hemoglobin adducts in lung cancer cases and controls. , 1991, Cancer research.

[57]  M. Butler,et al.  Frequency of urination and its effects on metabolism, pharmacokinetics, blood hemoglobin adduct formation, and liver and urinary bladder DNA adduct levels in beagle dogs given the carcinogen 4-aminobiphenyl. , 1991, Cancer research.

[58]  S. Tannenbaum,et al.  4-Aminobiphenyl hemoglobin adducts in fetuses exposed to the tobacco smoke carcinogen in utero. , 1991, Journal of the National Cancer Institute.

[59]  V. Lakshmi,et al.  Mechanism of peroxidative activation of the bladder carcinogen 2-amino-4-(5-nitro-2-furyl)-thiazole (ANFT): comparison with benzidine. , 1990, Carcinogenesis.

[60]  L. Ellwein,et al.  Proliferative and genotoxic cellular effects in 2-acetylaminofluorene bladder and liver carcinogenesis: biological modeling of the ED01 study. , 1990, Toxicology and applied pharmacology.

[61]  P. Vineis,et al.  Acetylation phenotype, carcinogen-hemoglobin adducts, and cigarette smoking. , 1990, Cancer research.

[62]  G. Talaska,et al.  Detection and characterization of carcinogen-DNA adducts in exfoliated urothelial cells from 4-aminobiphenyl-treated dogs by 32P-postlabelling and subsequent thin-layer and high-pressure liquid chromatography. , 1990, Carcinogenesis.

[63]  M. Butler,et al.  Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[64]  L. Garfinkel,et al.  Histologic changes in the urinary bladder in relation to cigarette smoking and use of artificial sweeteners , 1989, Cancer.

[65]  W. Weber,et al.  Purification and biochemical characterization of hepatic arylamine N-acetyltransferase from rapid and slow acetylator mice: identity with arylhydroxamic acid N,O-acyltransferase and N-hydroxyarylamine O-acetyltransferase. , 1989, Molecular pharmacology.

[66]  P. Vineis,et al.  Hemoglobin adducts of aromatic amines: associations with smoking status and type of tobacco. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[67]  J. Groopman,et al.  Immunochemical quantitation of DNA adducts derived from the human bladder carcinogen 4-aminobiphenyl. , 1988, Cancer research.

[68]  R. Edwards,et al.  A form of cytochrome P450 in man, orthologous to form d in the rat, catalyses the O-deethylation of phenacetin and is inducible by cigarette smoking. , 1988, British journal of clinical pharmacology.

[69]  D. Hein.  Acetylator genotype and arylamine-induced carcinogenesis. , 1988, Biochimica et biophysica acta.

[70]  J. Westra,et al.  Comparative carcinogenicity of the food pyrolysis product, 2-amino-5-phenylpyridine, and the known human carcinogen, 4-aminobiphenyl, in the neonatal B6C3F1 mouse. , 1988, Cancer letters.

[71]  D. Casciano,et al.  Identification of C8-modified deoxyinosine and N2- and C8-modified deoxyguanosine as major products of the in vitro reaction of N-hydroxy-6-aminochrysene with DNA and the formation of these adducts in isolated rat hepatocytes treated with 6-nitrochrysene and 6-aminochrysene. , 1987, Carcinogenesis.

[72]  S. Swaminathan,et al.  Quantitative assessments of the cytotoxicity of bladder carcinogens towards cultured normal human uroepithelial cells. , 1986, Carcinogenesis.

[73]  F. Kadlubar,et al.  Acetyl coenzyme A-dependent metabolic activation of N-hydroxy-3,2'-dimethyl-4-aminobiphenyl and several carcinogenic N-hydroxy arylamines in relation to tissue and species differences, other acyl donors, and arylhydroxamic acid-dependent acyltransferases. , 1986, Carcinogenesis.

[74]  F. Guengerich,et al.  Metabolic oxidation of carcinogenic arylamines by rat, dog, and human hepatic microsomes and by purified flavin-containing and cytochrome P-450 monooxygenases. , 1985, Cancer research.

[75]  D. Gaylor,et al.  Carcinogenesis of 4-aminobiphenyl in BALB/cStCrlfC3Hf/Nctr mice. , 1985, European journal of cancer & clinical oncology.

[76]  R. Pero,et al.  Adenosine diphosphate ribosyl transferase in marrow cells of patients with acute myeloid leukemia is related to differentiation and drug sensitivity. , 1985, Carcinogenesis.

[77]  R. Glashan,et al.  ROLE OF N-ACETYLTRANSFERASE PHENOTYPES IN BLADDER CARCINOGENESIS: A PHARMACOGENETIC EPIDEMIOLOGICAL APPROACH TO BLADDER CANCER , 1982, The Lancet.

[78]  F. Kadlubar,et al.  Prostaglandin endoperoxide synthetase-mediated metabolism of carcinogenic aromatic amines and their binding to DNA and protein. , 1982, Biochemical and biophysical research communications.

[79]  A. Ng,et al.  The initiation, progress, and diagnosis of dog bladder cancer induced by 4-aminobiphenyl. , 1978, Investigative urology.

[80]  J. Miller,et al.  Hepatic microsomal N-glucuronidation and nucleic acid binding of N-hydroxy arylamines in relation to urinary bladder carcinogenesis. , 1977, Cancer research.

[81]  W. Melick,et al.  Bladder cancer due to exposure to para-aminobiphenyl: a 17-year followup. , 1971, The Journal of urology.

[82]  M. Melamed,et al.  Further cytologic and histologic studies of bladder lesions in workers exposed to para-aminodiphenyl: progress report. , 1969, Journal of the National Cancer Institute.

[83]  R. Carter,et al.  Induction of hepatomas by 4-aminobiphenyl and three of its hydroxylated derivatives administered to newborn mice. , 1968, Journal of the National Cancer Institute.

[84]  D. Clayson,et al.  The carcinogenic action of 2-aminodiphenylene oxide and 4-aminodiphenyl on the bladder and liver of the C57 X IF mouse. , 1967, British Journal of Cancer.

[85]  W. Deichmann,et al.  SYNERGISM AMONG ORAL CARCINOGENS. 3. SIMULTANEOUS FEEDING OF FOUR BLADDER CARCINOGENS TO DOGS. , 1965, Industrial medicine & surgery.

[86]  D. Clayson,et al.  Correlation Between the Chemical Induction of Hyperplasia and of Malignancy in the Bladder Epithelium , 1965, British Journal of Cancer.

[87]  A. B. Hill.  The Environment and Disease: Association or Causation? , 1965, Proceedings of the Royal Society of Medicine.

[88]  M. Melamed,et al.  CARCINOGENESIS IN THE HUMAN URINARY BLADDER: OBSERVATIONS AFTER EXPOSURE TO PARA-AMINODIPHENYL. , 1965, The New England journal of medicine.

[89]  E. Miller,et al.  The N-Hydroxylation of 4-Acetylaminobiphenyl by the Rat and Dog and the Strong Carcinogenicity of N-Hydroxy-4-acetylaminobiphenyl in the Rat , 1961 .

[90]  W. Melick,et al.  The first reported cases of human bladder tumors due to a new carcinogen-xenylamine. , 1955, The Journal of urology.

[91]  D. C. Roberts,et al.  Tumours Of The Urinary Bladder in Dogs after Ingestion Of 4-Aminodiphenyl , 1954, British journal of industrial medicine.

[92]  D. C. Roberts,et al.  The Carcinogenic Action of 4-Aminodiphenyl and 3:2'-Dimethyl-4-Aminodiphenyl , 1952, British journal of industrial medicine.

[93]  E. Kriek.  Fifty years of research onN-acetyl-2-aminofluorene, one of the most versatile compounds in experimental cancer research , 2005, Journal of Cancer Research and Clinical Oncology.

[94]  Cancer Epidemiol Biomarkers Prev , 2004 .

[95]  J. Barrett,et al.  Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: allele frequencies, linkage disequilibrium and influence on caffeine metabolism. , 2003, British journal of clinical pharmacology.

[96]  U. Nseyo,et al.  Mutagenic outcome of the urinary carcinogen 4-aminobiphenyl is increased in acidic pH. , 2002, Environmental toxicology and pharmacology.

[97]  S. Swaminathan,et al.  Identification of N‐(deoxyguanosin‐8‐yl)‐4‐azobiphenyl by 32P‐postlabeling analyses of DNA in human uroepithelial cells exposed to proximate metabolites of the environmental carcinogen 4‐aminobiphenyl , 2002, Environmental and molecular mutagenesis.

[98]  C. Cordon-Cardo,et al.  Impact of alterations affecting the p53 pathway in bladder cancer on clinical outcome, assessed by conventional and array-based methods. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[99]  S. Swaminathan,et al.  DNA damage in human transitional cell carcinoma cells after exposure to the proximate metabolite of the bladder carcinogen 4‐aminobiphenyl , 2001, Environmental and molecular mutagenesis.

[100]  O Pelkonen,et al.  Metabolism of xenobiotics and chemical carcinogenesis. , 1999, IARC scientific publications.

[101]  T. Eling,et al.  Bioactivation of xenobiotics by prostaglandin H synthase. , 1991, Chemico-biological interactions.

[102]  M. Butler,et al.  Metabolic oxidation of the carcinogens 4-aminobiphenyl and 4,4'-methylene-bis(2-chloroaniline) by human hepatic microsomes and by purified rat hepatic cytochrome P-450 monooxygenases. , 1989, Cancer research.

[103]  C. M. Fraser.  The Merck veterinary manual. , 1986 .

[104]  D. Gaylor.  The ED01 study: summary and conclusions. , 1980, Journal of environmental pathology and toxicology.

[105]  D. Gaylor,et al.  Journal Abstracts , 1979, Journal of environmental pathology and toxicology.

[106]  Gaylor Dw,et al.  The ED01 study: summary and conclusions. , 1980 .

[107]  T Cairns,et al.  The ED01 study: introduction, objectives, and experimental design. , 1980, Journal of environmental pathology and toxicology.

[108]  W. MacDonald,et al.  The non-carcinogenicity of a single dose of 4-aminobiphenyl in the dog. , 1968, Food and cosmetics toxicology.

[109]  M. Melamed,et al.  Cytohistological observations on developing carcinoma of the urinary bladder in man , 1960 .

[110]  W. Deichmann,et al.  The carcinogenic action of p-aminobiphenyl in the dog; final report. , 1958, Industrial medicine & surgery.