2-Amino-1-methyl-6-phenylimidazo ,5-byridine (also known as PhIP) is one of the most abundant

heterocyclic amines Heterocyclic amines, also sometimes referred to as HCAs, are chemical compounds containing at least one heterocyclic ring, which by definition has atoms of at least two different elements, as well as at least one amine (nitrogen-containing) group. ...

(HCAs) found in cooked meat. PhIP is formed at high temperatures from the reaction between

creatine Creatine ( or ) is an organic compound with the nominal formula . It exists in various tautomers in solutions (among which are neutral form and various zwitterionic forms). Creatine is found in vertebrates, where it facilitates recycling of ...

creatinine Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass). Biological relevance Serum creatinine (a blood measurement) is an impor ...

(found in muscle meats),

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

, and sugar. PhIP formation increases with the temperature and duration of cooking and also depends on the method of cooking and the variety of meat being cooked. The U.S. Department of Health and Human Services National Toxicology Program has declared PhIP as "reasonably anticipated to be a human carcinogen". International Agency for Research on Cancer (IARC), part of World Health Organization, has classified PhIP as

IARC Group 2B carcinogen IARC group 2B substances, mixtures and exposure circumstances are those that have been classified as "possibly carcinogenic to humans" by the International Agency for Research on Cancer (IARC) as This category is used when there is limited evide ...

(i.e., possibly carcinogenic to humans). There is sufficient evidence in experimental animals, as well as

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

models, for the carcinogenicity of PhIP.a b Cross, A., & Sinha, R. (2004) Meat-Related Mutagens/Carcinogens in the Etiology of Colorectal Cancer. Environmental and Molecular Mutagenesis. 44:45-55.

Sources of PhIP

PhIP has been found in cooked beef, pork, chicken, and fish products. Exposure to PhIP depends on the eating habits of the individual and can vary up to 5000-fold. Exposure is also related to the type of meat, doneness, cooking method, and quantity consumed. Individual exposures can differ due to various anti-carcinogens in the diet. Different cooking methods for meat (broiling, grilling, frying, roasting, pan drippings) all contribute to formation of PhIP.

PhIP and cooking methods

Studies examining the amount of PhIP in cooked meats have shown that high levels of exposure are possible. Doneness levels of meat (rare, medium, well-done, and very well-done) are factors in the development of PhIP. Methods to reduce formation of PhIP in meats include decreasing the temperature at which the meat is cooked, decreasing the length of cooking time, pre-heating meat in the microwave oven (which reduces

), and marinating the meat.

Dietary intake of PhIP

Determining dietary intake of PhIP can be obtained by more or one ways. One method used is a Food Frequency Questionaries (FFQ) which surveys a population on their estimated consumption of cooked meats. Another method directly measures the quantity of PhIP in a cooked meat sample. However, because the formation of PhIP in cooked meat items is dependent on temperature, cooking time, and cooking method, variations do occur in the direct measurement method. Direct measurement methods have determined dietary intake levels of PhIP to range from 0.07-4.3 ng/kg per day.

Metabolism

Metabolic activation is required for PhIP to function as a

mutagen In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in ...

. Therefore, the cancer risk posed by PhIP depends on the extent at which PhIP is metabolized. After absorption, PhIP is converted to a genotoxic metabolite in the liver by Phase I enzyme N-oxidation by Cytochrome P-450 1A2 (

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

). PhIP can be further metabolized into a more potent metabolite through O-acetylation by hepatic or colonic

N-acetyltransferase ''N''-acetyltransferase (NAT) is an enzyme that catalyzes the transfer of acetyl groups from acetyl-CoA to arylamines, arylhydroxylamines and arylhydrazines. They have wide specificity for aromatic amines, particularly serotonin, and can also cat ...

1 (NAT1) and

N-acetyltransferase 2 N-acetyltransferase 2 (arylamine N-acetyltransferase), also known as NAT2, is an enzyme which in humans is encoded by the ''NAT2'' gene. Function This gene encodes a type of N-acetyltransferase. The NAT2 isozyme functions to both activate and ...

(NAT2), or by sulfotransferases. However, PhIP may also undergo a detoxification pathway through Phase II conjugation reaction via UDP-

glucuronosyltransferase Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UDPGT or UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecu ...

s (UGTs) to form N-glucuronide conjugates. PhIP's nitrenium ion intermediate is a powerful

electrophile In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively Electric charge, charged, have an ...

that has propensity to form C-8

guanine Guanine () (symbol G or Gua) is one of the four main nucleotide bases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside ...

adducts In chemistry, an adduct (; alternatively, a contraction of "addition product") is a product of a direct addition of two or more distinct molecules, resulting in a single reaction product containing all atoms of all components. The resultant is ...

with the

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

.Felton, J., et al. (1997). Health Risks of

Heterocyclic Amines Heterocyclic amines, also sometimes referred to as HCAs, are chemical compounds containing at least one heterocyclic ring, which by definition has atoms of at least two different elements, as well as at least one amine (nitrogen-containing) group. ...

. Mutation Research. 376: 37-41. In addition, some of these metabolic enzymes are inducible and have polymorphic variation.

displays a 40-fold variation in expression among humans and can be induced by smoking, diet, and chronic hepatitis. The expression of UGTs also displays inducibility; however, NATs do not. Individuals can be classified as either rapid or slow N-oxidizers and O-acetylators by assessing

and NAT2 activities. Individuals with the rapid

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...

of either

or NAT2 metabolize PhIP more effectively and are therefore at greater risk of PhIP's carcinogenic metabolite and could be at a higher risk of cancer.

Animal studies and PhIP

Rats were fed PhIP at concentrations of 25, 100, and 200 ppm. The rats gained weight throughout the experiment, but feeding concentration of PhIP remained constant. Rats were fed PhIP ''ad libitum'' at concentrations of 12.5 and 50ppm. Rats developed mammary tumors at each concentration of PhIP administered. An ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' study found mice injected with 5, 10, 12, 18, 20, 24, 28, 32, or 36 mg/kg bw showed a strong correlation between consumption of PhIP and genetic damage.

Risk assessments for PhIP

There is no dose f PhIPwithout effect. Therefore, a margin of exposure (MOE) based on the benchmark lower confidence limit (BMDL) reference has been developed for PhIP in relation to prostate and mammary carcinomas.

Associated cancers

Numerous

and

studies have demonstrated that PhIP is a potent

and can induce tumors of multiple sites in animal models. PhIP was positive in bacterial (

Ames AMES, short Air Ministry Experimental Station, was the name given to the British Air Ministry's radar development team at Bawdsey Manor (afterwards RAF Bawdsey) in the immediate pre-World War II era. The team was forced to move on three occasion ...

) test and induced chromosomal abnormalities in human and Chinese hamster cells

. PhIP has also formed

in both rats and monkeys.a b Carthew, P., DiNovi, M., & Setzer, W. (2010).Application of the Margin of Exposure (MOE) approach to substances in food that are genotoxic and carcinogenic Example: CAS No: 105650-23-5 PhIP (2-amino-methyl-6-penylimidazo ,5-byridine). Food and Chemical Toxicology. 48: S98-S105. PhIP has been tested for carcinogenicity in both mice and rats by oral administration. Increases in

lymphomas Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...

were seen in mice and increases in

adenocarcinomas Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ; AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, o ...

of the small and large intestine in males and mammary

in female were seen in rats. Also, an increasing number of

epidemiological Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and Risk factor (epidemiology), determinants of health and disease conditions in a defined population, and application of this knowledge to prevent dise ...

studies have evaluated the association of well-done meat intake and HCA exposure with cancer risk in humans. In general, these studies have reported that high intake of well-done and/or high exposure to PhIP may be associated with cancer of the colorectum, breast, prostate, pancreas, lung, stomach, and esophagus. PhIP has been shown to induce

and mutations. These

have been found in a wide variety of sensitive tissues and organs such as the colon. However,

also formed in sites that did not commonly form tumors, such as the kidneys. In humans receiving a dose of PhIP equivalent to that found in very well-done chicken,

and protein

were formed in the colon and blood. However, the

were unstable and declined over a 24-hour period.Dingley, K., et al. (1999).

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 ,5-byridine. Cancer Epidemiol Biomarkers Prev. 8:507-512.

References

{{DEFAULTSORT:Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, 2- Aromatic amines