Biomaterial Database

Metabolism of the food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the rat and other rodents. 1995

J Alexander, and B H Fossum, and R Reistad, and J A Holme

Department of Environmental Medicine, National Institute of Public Health, Oslo, Norway.

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant compound of the amino-imidazoazaarens (AIA) group of muta-/carcinogens isolated from the crust of fried meat. PhIP is principally activated via P450IA2 dependent N2-hydroxylation. A major metabolic pathway is N2-glucuronidation of the proximate 2-hydroxyamino-PhIP metabolite and excretion via bile to the intestine. After bacterial hydrolysis the proximate metabolite may be esterified by the intestinal cells and cause genetic damage. 2-Hydroxyamino-PhIP formed in vivo may be further oxidized presumably to 2-nitro-PhIP which reacts directly with glutathione through substitution of the nitro group. Detoxification is principally via P450IA1 dependent ring-hydroxylation followed by sulfation or glucuronidation. Direct glucuronidation also occurs. PhIP metabolism was examined in freshly isolated hepatocytes from rat, mouse, hamster and guinea pig. Activation was evaluated by the total level of covalent binding of PhIP to macromolecules. Rat hepatocytes had the lowest rate of metabolism, both to reactive and detoxified metabolites. The major products were 4'PhIP-sulfate, PhIP-glucuronide and 2-hydroxyamino-PhIP glucuronide, whereas in the mouse hepatocytes mainly 4'PhIP-sulfate was found. The level of covalent binding in the mouse hepatocytes exceeded those of the rat. An extensive metabolism was seen in guinea pig hepatocytes, the major products being 4'PhIP-sulfate, 4'-O-PhIP glucuronide, PhIP-glucuronide and 2-hydroxyamino-PhIP-glucuronide. The relative amount of PhIP covalently bound to macromolecules in guinea pig hepatocytes was low. Hamster hepatocytes had the highest level of covalently bound PhIP. The main metabolites were 4'PhIP-sulfate, 4'O-PhIP-glucuronide and PhIP-glucuronide. Minor amounts of 2-hydroxyamino-PhIP-glucuronide was produced in the hamster. Several unknown PhIP metabolites were formed in the hamster and guinea pig. Direct detoxification of PhIP and further metabolism of 2-hydroxyamino-PhIP to reactive and/or detoxified metabolites are important for the resulting covalent binding.

UI	MeSH Term	Description	Entries
D007093	Imidazoles	Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
D008658	Inactivation, Metabolic	Reduction of pharmacologic activity or toxicity of a drug or other foreign substance by a living system, usually by enzymatic action. It includes those metabolic transformations that make the substance more soluble for faster renal excretion.	Detoxication, Drug, Metabolic,Drug Detoxication, Metabolic,Metabolic Detoxication, Drug,Detoxification, Drug, Metabolic,Metabolic Detoxification, Drug,Metabolic Drug Inactivation,Detoxication, Drug Metabolic,Detoxication, Metabolic Drug,Detoxification, Drug Metabolic,Drug Inactivation, Metabolic,Drug Metabolic Detoxication,Drug Metabolic Detoxification,Inactivation, Metabolic Drug,Metabolic Drug Detoxication,Metabolic Inactivation
D010084	Oxidation-Reduction	A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471).	Redox,Oxidation Reduction
D002273	Carcinogens	Substances that increase the risk of NEOPLASMS in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included.	Carcinogen,Oncogen,Oncogens,Tumor Initiator,Tumor Initiators,Tumor Promoter,Tumor Promoters,Initiator, Tumor,Initiators, Tumor,Promoter, Tumor,Promoters, Tumor
D005502	Food	Substances taken in by the body to provide nourishment.	Foods
D005965	Glucuronates	Derivatives of GLUCURONIC ACID. Included under this heading are a broad variety of acid forms, salts, esters, and amides that include the 6-carboxy glucose structure.	Glucosiduronates,Glucuronic Acids,Acids, Glucuronic
D006224	Cricetinae	A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.	Cricetus,Hamsters,Hamster
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D001711	Biotransformation	The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alterations may be divided into METABOLIC DETOXICATION, PHASE I and METABOLIC DETOXICATION, PHASE II.