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Grant Details

Grant Number: 5R01CA055751-05 Interpret this number
Primary Investigator: Lang, Nicholas
Organization: University Of Arkansas Med Scis Ltl Rock
Project Title: Acetylation and N-Oxidation in Colorectal Cancer
Fiscal Year: 1998
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Abstract

A case-control study to examine the independent and combined efforts of arylamine acetylator status and N-oxidation status and heterocyclic and aromatic amine exposure on the risk of development of colorectal cancer is proposed. The specific aims of this grant application are: To confirm the initial findings of our pilot study regarding the roles of heterocyclic and aromatic amine metabolism and exposure as putative risk factors from the diet or the environment. The sources amine metabolism and exposure as putative risk factors from the diet or the environment. The sources of heterocyclic and aromatic amines to be studied are cigarette smoking, diet and cooking methods; the metabolic pathways to be studied include heterocyclic amine N-oxidation status and O-acetylation status. The experimental design involves the conduct of arylamine acetyltransferase and arylamine N-oxidation phenotyping on patients with a history of carcinoma of the colorectum and on control patients. This phenotyping will be performed using a single dose of caffeine administered as an instant coffee drink and will involve the collection of a single urine specimen. The caffeine metabolites will be measured by HPLC and the phenotype determined by the radio of AFMU/1X for acetylation and [17U+17X]/137X for N-oxidation. The source of exposure will be determined by the use of the Willett Food Frequency Questionnaire which will provide estimates of total energy intake and micronutrients. Additional information regarding specific exposure to amines will be gathered in a personal interview that covers smoking history, dietary practices (e.g., char-broiled, roasted or microwaved meat), occupational history, medical and family history and basic demographic information. We hypothesize that heterocyclic and aromatic amines are colon carcinogens for humans. These compounds occur primarily in cooked fish and meat and are also present in cigarette smoke. Based on results from our pilot study, we hypothesize that the group at greatest susceptibility for the development of colorectal cancer will be those people who are both rapid acetylation and rapid N-oxidation phenotypes, who are exposed to high levels of arylamines, for example, red mead cooked well done. This study should provide information on relevant individual risk of factors that could serve as a basis for attempts to modify high risk behavior (e.g., environmental exposure and dietary practices) among those at greatest risk to develop cancer. It is a unique opportunity for collaboration between laboratory scientist and traditional epidemiologists in developing a new approach to cancer risk identification.

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Publications

The urinary metabolite profile of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is predictive of colon DNA adducts after a low-dose exposure in humans.
Authors: Malfatti M.A. , Dingley K.H. , Nowell-Kadlubar S. , Ubick E.A. , Mulakken N. , Nelson D. , Lang N.P. , Felton J.S. , Turteltaub K.W. .
Source: Cancer research, 2006-11-01; 66(21), p. 10541-7.
PMID: 17079477
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CYP3A43 Pro(340)Ala polymorphism and prostate cancer risk in African Americans and Caucasians.
Authors: Stone A. , Ratnasinghe L.D. , Emerson G.L. , Modali R. , Lehman T. , Runnells G. , Carroll A. , Carter W. , Barnhart S. , Rasheed A.A. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2005 May; 14(5), p. 1257-61.
PMID: 15894682
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Association of SULT1A1 phenotype and genotype with prostate cancer risk in African-Americans and Caucasians.
Authors: Nowell S. , Ratnasinghe D.L. , Ambrosone C.B. , Williams S. , Teague-Ross T. , Trimble L. , Runnels G. , Carrol A. , Green B. , Stone A. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2004 Feb; 13(2), p. 270-6.
PMID: 14973106
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Novel markers of susceptibility to carcinogens in diet: associations with colorectal cancer.
Authors: Sweeney C. , Coles B.F. , Nowell S. , Lang N.P. , Kadlubar F.F. .
Source: Toxicology, 2002-12-27; 181-182, p. 83-7.
PMID: 12505289
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Analysis of total meat intake and exposure to individual heterocyclic amines in a case-control study of colorectal cancer: contribution of metabolic variation to risk.
Authors: Nowell S. , Coles B. , Sinha R. , MacLeod S. , Luke Ratnasinghe D. , Stotts C. , Kadlubar F.F. , Ambrosone C.B. , Lang N.P. .
Source: Mutation research, 2002-09-30; 506-507, p. 175-85.
PMID: 12351157
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CYP2A6 activity determined by caffeine phenotyping: association with colorectal cancer risk.
Authors: Nowell S. , Sweeney C. , Hammons G. , Kadlubar F.F. , Lang N.P. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2002 Apr; 11(4), p. 377-83.
PMID: 11927498
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The role of human glutathione S-transferases (hGSTs) in the detoxification of the food-derived carcinogen metabolite N-acetoxy-PhIP, and the effect of a polymorphism in hGSTA1 on colorectal cancer risk.
Authors: Coles B. , Nowell S.A. , MacLeod S.L. , Sweeney C. , Lang N.P. , Kadlubar F.F. .
Source: Mutation research, 2001-10-01; 482(1-2), p. 3-10.
PMID: 11535243
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Validity of an ELISA for N-acetyltransferase-2 (NAT2) phenotyping.
Authors: Wong P. , Banerjee K. , Massengill J. , Nowell S. , Lang N. , Leyland-Jones B. .
Source: Journal of immunological methods, 2001-05-01; 251(1-2), p. 1-9.
PMID: 11292476
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Relationship of phenol sulfotransferase activity (SULT1A1) genotype to sulfotransferase phenotype in platelet cytosol.
Authors: Nowell S. , Ambrosone C.B. , Ozawa S. , MacLeod S.L. , Mrackova G. , Williams S. , Plaxco J. , Kadlubar F.F. , Lang N.P. .
Source: Pharmacogenetics, 2000 Dec; 10(9), p. 789-97.
PMID: 11191883
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An allele-specific polymerase chain reaction method for the determination of the D85Y polymorphism in the human UDP-glucuronosyltransferase 2B15 gene in a case-control study of prostate cancer.
Authors: MacLeod S.L. , Nowell S. , Plaxco J. , Lang N.P. .
Source: Annals of surgical oncology, 2000 Dec; 7(10), p. 777-82.
PMID: 11129427
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In vivo human metabolism of [2-14C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).
Authors: Lang N.P. , Nowell S. , Malfatti M.A. , Kulp K.S. , Knize M.G. , Davis C. , Massengill J. , Williams S. , MacLeod S. , Dingley K.H. , et al. .
Source: Cancer letters, 1999-09-01; 143(2), p. 135-8.
PMID: 10503892
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DNA and protein adduct formation in the colon and blood of humans after exposure to a dietary-relevant dose of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.
Authors: Dingley K.H. , Curtis K.D. , Nowell S. , Felton J.S. , Lang N.P. , Turteltaub K.W. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 1999 Jun; 8(6), p. 507-12.
PMID: 10385140
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Glucuronidation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4, 5-b]pyridine by human microsomal UDP-glucuronosyltransferases: identification of specific UGT1A family isoforms involved.
Authors: Nowell S.A. , Massengill J.S. , Williams S. , Radominska-Pandya A. , Tephly T.R. , Cheng Z. , Strassburg C.P. , Tukey R.H. , MacLeod S.L. , Lang N.P. , et al. .
Source: Carcinogenesis, 1999 Jun; 20(6), p. 1107-14.
PMID: 10357796
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The identification of [2-(14)C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine metabolites in humans.
Authors: Malfatti M.A. , Kulp K.S. , Knize M.G. , Davis C. , Massengill J.P. , Williams S. , Nowell S. , MacLeod S. , Dingley K.H. , Turteltaub K.W. , et al. .
Source: Carcinogenesis, 1999 Apr; 20(4), p. 705-13.
PMID: 10223203
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Human cytochrome P4501A2.
Authors: Landi M.T. , Sinha R. , Lang N.P. , Kadlubar F.F. .
Source: IARC scientific publications, 1999; (148), p. 173-95.
PMID: 10493258
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Identification of enzymes responsible for the metabolism of heme in human platelets.
Authors: Nowell S.A. , Leakey J.E. , Warren J.F. , Lang N.P. , Frame L.T. .
Source: The Journal of biological chemistry, 1998-12-11; 273(50), p. 33342-6.
PMID: 9837908
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Thomas G. Orr Memorial Lectureship. Colon cancer from etiology to prevention.
Authors: Lang N.P. .
Source: American journal of surgery, 1997 Dec; 174(6), p. 578-82.
PMID: 9409576
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Polymorphisms of CYP1A1 and GSTM1 influence the in vivo function of CYP1A2.
Authors: MacLeod S. , Sinha R. , Kadlubar F.F. , Lang N.P. .
Source: Mutation research, 1997-05-12; 376(1-2), p. 135-42.
PMID: 9202749
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