Amongst the mutagens found in fried meat, 2-amino-3-methylimidazo [4,5-f] quinaline (IQ) is a representative compound. IQ has recently been shoun to be a powerful carcinogen in mice and in rats. A number of important target organs were affected in rats, including the intestinal tract, mammary gland, ear duct, and pancreas, as well as other organs to a lesser degree. Of relevance, is the specificity for intestinal tract and mammary gland since these findings underwrite the working hypothesis that IQ and related compounds may be the genotoxic, DNA-reactive carcinogens involved in human nutritional carcinogenesis. Based on current knowledge of the metabolism of related carcinogenic arylamines, the hypothesis can be formulated that IQ undergoes metabolism to a N-hydroxy derivative, or a N-acety 1-N-hydroxy derivative, further converted to a transport form such as a glucuronide. This complex may be hydrolyzed, and the released aglycone further metabolized to DNA-reactive forms in target tissues. Thus, research on the mode of action of IQ through detailed studies of its metabolism is of great contemporary importance. The overall fate of IQ will be studied using the isotopically labeled chemical in animals as a function of age, sex, and dosage of IQ. Furthermore, possible modification of metobolism by chronic exposure to IQ, fed for ten weeks and for six months, will be examined. Interaction with cellular macromolecules, including DNA will be determined, including binding as a function of dosage and time. Parallel studies will be conducted on cells and cell fractions, with initial emphasis on liver and intestinal tract, again in animals pretreated with unlabeled IQ and naive animals of the same age. The dosages used will include the level that induces cancer in animals and lower level. This approach is designed to provide key background information on the mode of action of a newly discovered class of carcinogens with extensive human intake.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042381-03
Application #
3183612
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1986-04-01
Project End
1989-08-31
Budget Start
1988-04-01
Budget End
1989-08-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Institute for Cancer Prevention
Department
Type
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Weisburger, J H (1996) Human protection against non-genotoxic carcinogens in the US without the Delaney Clause. Exp Toxicol Pathol 48:201-8
Weisburger, J H (1996) The 37 year history of the Delaney Clause. Exp Toxicol Pathol 48:183-8
Apostolides, Z; Balentine, D A; Harbowy, M E et al. (1996) Inhibition of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) mutagenicity by black and green tea extracts and polyphenols. Mutat Res 359:159-63
Apostolides, Z; Weisburger, J H (1995) Screening of tea clones for inhibition of PhIP mutagenicity. Mutat Res 326:219-25
Kakiuchi, H; Watanabe, M; Ushijima, T et al. (1995) Specific 5'-GGGA-3'-->5'-GGA-3' mutation of the Apc gene in rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Proc Natl Acad Sci U S A 92:910-4
Weisburger, J H; Rivenson, A; Kingston, D G et al. (1995) Dietary modulation of the carcinogenicity of the heterocyclic amines. Princess Takamatsu Symp 23:240-50
Weisburger, J H (1994) Does the Delaney Clause of the U.S. Food and Drug laws prevent human cancers? Fundam Appl Toxicol 22:483-93
Weisburger, J H (1994) Practical approaches to chemoprevention of cancer. Drug Metab Rev 26:253-60
Weisburger, J H; Rivenson, A; Hard, G C et al. (1994) Role of fat and calcium in cancer causation by food mutagens, heterocyclic amines. Proc Soc Exp Biol Med 205:347-52
Weisburger, J H; Braley, J; Reinhardt, J et al. (1994) The role of fat and calcium in the production of foci of aberrant crypts in the colon of rats fed 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine. Environ Health Perspect 102 Suppl 6:53-5

Showing the most recent 10 out of 28 publications