Epidemiological evidence strongly suggests that diet is an important factor in the etiology of human cancer but the mechanisms underlying this association are largely unknown. Some foods contain naturally occurring mutagens whilst others acquire them because of contamination by micro-organisms. Recently, attention has focussed on the generation of mutagenic chemicals in food, particularly meat and fish, during cooking. Amongst these numerous mutagens are the heteroaromatic amines (HA's) of the carboline and imidoquinoline type. The overall purpose of this project is to conduct an in-depth study of HA's in cooked food. The data generated will help determine the relevance of these chemicals to human cancer and give a basis for suggesting changes in diet if these are deemed necessary. The specific objectives are: 1. To develop assays, based on combined gas or liquid chromatography-mass spectrometry (GC-MS or LC-MS), to measure mutagenic HA's in foods and the unchanged amines and their major metabolites in body fluids. 2. To determine the extent of absorption, the metabolic fate and the routes of excretion of HA's and their metabolites in laboratory animals. 3. To compare the metabolism of these amines by human and animal tissues in order to identify a major metabolite which may be used to determine the body burden of these compounds in subjects consuming HA's in food. 4. To confirm previous results that the enzymic activation of these amines is mediated by the cytochrome P-450 system and involves the formation of intermediate N-hydroxy derivatives. 5. To determine the fate of the mutagenic intermediates in hepatocytes from rats, dogs and man in order to identify possible excretory metabolites which may be used to assess the extent of metabolism via this pathway in vivo in animals and in man. 6. Using the information gathered in 1 - 5, to establish methods to measure the absorption and metabolic activation of HA's from food consumed by human volunteers and to identify factors which influence these parameters.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA040895-02
Application #
3181210
Study Section
(SSS)
Project Start
1985-09-30
Project End
1988-07-31
Budget Start
1986-09-30
Budget End
1987-07-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of London
Department
Type
DUNS #
City
London
State
Country
United Kingdom
Zip Code
Gooderham, N J; Murray, S; Lynch, A M et al. (1997) Assessing human risk to heterocyclic amines. Mutat Res 376:53-60
Gooderham, N J; Murray, S; Lynch, A M et al. (1996) Heterocyclic amines: evaluation of their role in diet associated human cancer. Br J Clin Pharmacol 42:91-8
Rich, K J; Zhao, K; Davies, D S et al. (1996) Developmental changes in hepatic activation of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in rabbit. Carcinogenesis 17:555-8
Davies, D S; Gooderham, N J; Murray, S et al. (1996) Chemical methods for assessing systemic exposure to dietary heterocyclic amines in man. Arch Toxicol Suppl 18:251-8
Davies, D S; Gooderham, N J; Murray, S et al. (1995) Systemic exposure to dietary heterocyclic amines in man. Princess Takamatsu Symp 23:190-6
Boobis, A R; Gooderham, N J; Rich, K J et al. (1995) Enzymatic studies of the activation of heterocyclic food mutagens in man. Princess Takamatsu Symp 23:134-44
Zhao, K; Murray, S; Davies, D S et al. (1994) Metabolism of the food derived mutagen and carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) by human liver microsomes. Carcinogenesis 15:1285-8
Zhao, K; Boobis, A R; Davies, D S et al. (1994) The role of CYP1A enzymes in murine activation of the cooked food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Biochem Soc Trans 22:128S
Boobis, A R; Lynch, A M; Murray, S et al. (1994) CYP1A2-catalyzed conversion of dietary heterocyclic amines to their proximate carcinogens is their major route of metabolism in humans. Cancer Res 54:89-94
Banning, D P; O'Farrell, F; Gooderham, N J (1993) Activation of the food derived carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline by rat pleural cavity inflammatory cells. Carcinogenesis 14:2457-62

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