2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine

2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
IUPAC name 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
Other names PhIP
Identifiers
CAS number	105650-23-5 Y
PubChem	1530
ChemSpider	1476 Y
DrugBank	DB08398
ChEMBL	CHEMBL1213271 Y=
Jmol-3D images	Image 1
SMILES n1cc(cc2c1nc(n2C)N)c3ccccc3
InChI InChI=1S/C13H12N4/c1-17-11-7-10(9-5-3-2-4-6-9)8-15-12(11)16-13(17)14/h2-8H,1H3,(H2,14,15,16) Y= Key: UQVKZNNCIHJZLS-UHFFFAOYSA-N Y= InChI=1/C13H12N4/c1-17-11-7-10(9-5-3-2-4-6-9)8-15-12(11)16-13(17)14/h2-8H,1H3,(H2,14,15,16) Key: UQVKZNNCIHJZLS-UHFFFAOYAX
Properties
Molecular formula	C13H12N4
Molar mass	224.26 g mol−1
Appearance	Off-white solid
Density	1.3 gcm−3
Melting point	300 °C, 573 K, 572 °F
Boiling point	468.9 °C, 742 K, 876 °F
Solubility in water	407.1 mg/L
Hazards
Main hazards	T
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is one of the most abundant heterocyclic amines (HCAs) in cooked meat. It is classified as a IARC Group 2B carcinogen, possibly carcinogenic to humans,^[1] and is considered "reasonably anticipated to be a human carcinogen" by the U.S. Department of Health and Human Services National Toxicology Program. ^[2] PhIP is formed at high temperatures from the reaction between creatine or creatinine (found in muscle meats), amino acids, and sugar. PhIP formation increases with the temperature and duration of cooking and also depends on the method of cooking, as well as the variety of meat being cooked. There is inadequate evidence in humans that PhIP is carcinogenic, however, there is sufficient evidence in experimental animals, as well as in vitro models, for the carcinogenicity of PhIP.^[3]

Sources of PhIP

PhIP has been found in cooked beef, pork, chicken, and fish products at concentrations up to 70 ng/g.^[1] Estimates of PhIP intake, from the HCA database, suggest that the mean daily intake of PhIP is between 43 and 110 ng/day.^[4] However, exposure to PhIP depends on the eating habits of the individual and can vary up to 5000-fold. This exposure is related to the type of meat, doneness, cooking method, and quantity consumed. PhIP can be quantitatively measured as low as 0.1 ppb in cooked ground meat and chicken and up to 500 ppb in well-done flame-grilled chicken. Individual exposures can also differ due to various anti-carcinogens in the diet. Fiber or chlorophyllin, which directly bind to PhIP and prevent absorption, flavonoids, known inhibitors of metabolic activation, and substances that prevent formation of the carcinogen during cooking further complicate the exposure assessment to PhIP. Thus, the dose (exposure) plays a major role in individual risk related to PhIP and merely understanding the degree of doneness of the meat products may not be adequate.^[5]

PhIP and cooking methods

Early studies looking at the amount of PhIP in cooked meats have shown that a high level of exposure is possible. However, more recent studies estimate exposure to PhIP and other HCAs through intake questionnaires linked to an HCA database. This database was created by cooking different types of meats with a variety of different cooking methods to a range of doneness levels (rare, medium, well-done, and very well-done). The measured values of PhIP varied with the cut of beef, cooking method, and doneness level. In general, PhIP was the predominant HCA form.^[6][7][8][9] To reduce the formation of PhIP and other HCAs in meat, reduce the temperature and the length of cooking time or pre-heat the meat in the microwave oven, which removes creatine, a building block in the formation of PhIP.^[10]

^[11]

Marination of chicken in lemon juice reduces the levels of PhIP by 98%, whereas marination in soy sauce appears to increase the levels.^[12]

Metabolism

Metabolic activation is required for PhIP to function as a mutagen, 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). PhIP can be further metabolized into a more potent metabolite through O-acetylation by hepatic or colonic N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2), or by sulfotransfereases. However, PhIP may also undergo a detoxification pathyway through Phase II conjugation reaction via UDP-glucuronosyltransferases (UGTs) to form N-glucuronide conjugates.^[3] PhIP's nitrenium ion intermediate is a powerful electrophile that has propensity to form C-8 guanine adducts with the DNA. ^[13] In addition, some of these metabolic enzymes are inducible and have polymorphic variation. CYP1A2 displays a 40-fold variation in expression among humans and can be induced by smoking, diet, and chronic hepatitis.^[14] The expression of UGTs also displays inducability, however NATs do not. Individuals can be classified as either rapid or slow N-oxidizers and O-acetylators by assessing CYP1A2 and NAT2 activities.^[15] Individuals with the rapid phenotype of either CYP1A2 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.

Associated cancers

Numerous in vivo and in vitro studies have demonstrated that PhIP is a potent mutagen and can induce tumors of multiple sites in animal models. PhIP was positive in bacterial (Ames) test and induced chromosomal abnormalities in human and Chinese hamster cells in vitro. PhIP has also formed DNA adducts in vivo in both rats and monkeys.^[16] PhIP has been tested for carcinogenicity in both mice and rats by oral administration. Increases in lymphomas were seen in mice and increases in adenocarcinomas of the small and large intestine in males and mammary adenocarcinomas in female were seen in rats.^[16] Also, an increasing number of epidemiological 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.^[17]

PhIP has been shown to induce DNA adducts and mutations. These adducts have been found in a wide variety of sensitive tissues and organs such as the colon. However, adducts 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, DNA and protein adducts were formed in the colon and blood, however the adducts were unstable and declined over a 24 hour period.^[18]

References