The overall objective of this program of research is to conduct a thorough study of the absorption and metabolic activation in man of the major mutagens, MeIQx, DiMeIQx and PhIP, produced during the cooking of beef. Together, these compounds account for 60% of the mutagenicity of cooked meat. The results of these studies should help in the assessment of the relevance of these compounds to human cancer.
The specific aims are: 1. To measure the levels of MeIQx, and DiMeIQx in typical British and American diets to obtain estimates of the average daily intake (ADI) of these amines. The compound will be assayed using a highly specific and sensitive gas chromatographic-mass spectrometric GCMS method developed in this laboratory. 2. To assess the absorption of MeIQx and DiMeIQx from meat by measurement of the unchanged amines, or their major metabolites, in urine in human volunteers. In preliminary studies we have demonstrated that the GCMS assay developed for MeIQx is sufficiently sensitive for this purpose (see Progress Report). 3. To develop strategies to assess the degree of in vivo conversion of MeIQx and DiMeIQx to their reactive metabolites in man. A number of possible methods will be investigated, including the identification of a metastable metabolite of the reactive intermediate, and determination of adducts with haemoglobin or DNA. 4. To assess, by the methods to be developed above, the possible modifying influence of foods not containing MeIQx or DiMeIQx (e.g. high-fibre vegetables, vitamin c rich fruit, brassicaceous vegetables) on the absorption and/or activation of these amines. 5. To assess the body burden of MeIQx and DiMeIQx in volunteers eating typical British and American diets. 6. To determine in vivo, the extent to which the absorption and activation of MeIQx and DiMeIQx vary amongst individuals, and within an individual. To assess the effects of environmental factors such as cigarette smoking and alcohol consumption on the activation of the amines in vivo. 7. To develop a GCMS assay for PHIP in foods and body fluids and to apply this method in studies similar to those described above for MeIQx.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA040895-06
Application #
3181213
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1985-09-30
Project End
1993-08-31
Budget Start
1991-09-01
Budget End
1993-08-31
Support Year
6
Fiscal Year
1991
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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