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Revision as of 10:13, 17 February 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{chembox}} taken from revid 470704318 of page 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine for the Chem/Drugbox validation project (updated: 'DrugBank', 'ChEMBL', 'StdInCh...		Latest revision as of 02:18, 16 April 2024 edit Citation bot (talk | contribs)Bots5,391,531 edits Alter: issue, doi, url. URLs might have been anonymized. Formatted dashes. | Use this bot. Report bugs. | Suggested by Jay8g | Category:CS1 errors: DOI | #UCB_Category 3/4
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	{{ambox | text = This page contains a copy of the infobox ({{tl|chembox}}) taken from revid of page ] with values updated to verified values.}}
	{{Chembox		{{Chembox
			| Verifiedfields = changed
	| ImageFile_Ref = {{chemboximage|correct|??}}
			| Watchedfields = changed
			| verifiedrevid = 477343434
			| ImageFile_Ref = {{chemboximage|correct|??}}
	| ImageFile = PhIP.svg		| ImageFile = PhIP.svg
	| ImageName = PhIP		| ImageName = PhIP
			| PIN = 1-Methyl-6-phenyl-1''H''-imidazopyridin-2-amine
	| IUPACName = 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
	| OtherNames = PhIP		| OtherNames = PhIP
	| Section1 = {{Chembox Identifiers		|Section1={{Chembox Identifiers
			| ChEBI_Ref = {{ebicite|changed|EBI}}
	| verifiedrevid = 443663905
			| DrugBank_Ref = <!--{{drugbankcite|correct|drugbank}}-->
	| ChEBI_Ref =
	| ChEBI =
	| DrugBank_Ref =
	| DrugBank = DB08398		| DrugBank = DB08398
	| SMILES =		| SMILES = n1cc(cc2c1nc(n2C)N)c3ccccc3
	| ChemSpiderID_Ref =		| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 1476		| ChemSpiderID = 1476
	| PubChem = 1530		| PubChem = 1530
	| UNII_Ref =		| ChEBI = 76290
			| UNII_Ref = {{fdacite|changed|FDA}}
	| UNII =
			| UNII = 909C6UN66T
	| KEGG_Ref =
			| KEGG_Ref = {{keggcite|correct|kegg}}
	| KEGG =		| KEGG =
			| 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)
	| InChI =
	| InChIKey =		| InChIKey = UQVKZNNCIHJZLS-UHFFFAOYAX
	| ChEMBL_Ref =		| ChEMBL_Ref = {{ebicite|correct|EBI}}=
	| ChEMBL = 1213271		| ChEMBL = 1213271
	| StdInChI_Ref =		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}=
	| StdInChI = 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)		| StdInChI = 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)
	| StdInChIKey_Ref =		| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}=
	| StdInChIKey = UQVKZNNCIHJZLS-UHFFFAOYSA-N		| StdInChIKey = UQVKZNNCIHJZLS-UHFFFAOYSA-N
	| CASNo_Ref = {{cascite|correct|CAS}}		| CASNo_Ref = {{cascite|correct|CAS}}
	| CASNo = 105650-23-5		| CASNo = 105650-23-5
	| RTECS =		| RTECS =
	}}		}}
	| Section2 = {{Chembox Properties		|Section2={{Chembox Properties
	| C=13|H=12|N=4		| C=13 | H=12 | N=4
	| Appearance = Off-white solid		| Appearance = Off-white solid
	| Density = 1.3 gcm<sup>−3</sup>		| Density = 1.3 gcm<sup>−3</sup>
	| Solubility = 407.1 mg/L		| Solubility = 407.1 mg/L
	| MeltingPtC = 300		| MeltingPtC = 300
	| BoilingPtC = 468.9		| BoilingPtC = 468.9
	| pKa =		| pKa =
	| pKb =		| pKb =
	| Viscosity =		| Viscosity =
	}}		}}
	| Section3 = {{Chembox Structure		|Section3={{Chembox Structure
	| MolShape =		| MolShape =
	| Coordination =		| Coordination =
	| CrystalStruct =		| CrystalStruct =
	| Dipole =		| Dipole =
	}}		}}
	| Section7 = {{Chembox Hazards		|Section7={{Chembox Hazards
	| ExternalMSDS =		| ExternalSDS =
	| MainHazards = T		| MainHazards = T
	| FlashPt =		| FlashPt =
	| RPhrases =
	| SPhrases =
	}}		}}
	| Section8 = {{Chembox Related		|Section8={{Chembox Related
	| OtherAnions =		| OtherAnions =
	| OtherCations =		| OtherCations =
	| OtherCpds =		| OtherCompounds =
	}}		}}
	}}		}}
			{{About|heterocyclic amines|pleckstrin homology domain-interacting protein|Pleckstrin homology domain}}
			'''PhIP''' ('''2-Amino-1-methyl-6-phenylimidazopyridine''') is one of the most abundant ] (HCAs) in cooked meat. PhIP is formed at high temperatures from the reaction between ] or ] (found in muscle meats), ], 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".<ref>U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. (2011). Report on Carcinogens, 12th ed., p. 222.</ref> International Agency for Research on Cancer (IARC), part of World Health Organization, has classified PhIP as ] (i.e., possibly carcinogenic to humans).<ref>a b International Agency for Research on Cancer (IARC) (1997) PhIP (2-amino-1-methyl-6-phenylimidazopyridine)(Group 2B). Summaries & Evaluations. http://www.inchem.org/documents/iarc/vol56/08-phip.html</ref> There is sufficient evidence in experimental animals, as well as ] models, for the carcinogenicity of PhIP.<ref name="cross">a b Cross, A., & Sinha, R. (2004) Meat-Related Mutagens/Carcinogens in the Etiology of Colorectal Cancer. Environmental and Molecular Mutagenesis. 44:45-55.</ref>
			== 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.<ref name="Felton et al. 1997">{{cite journal |last1=Felton |first1=James |title=Health Risks of Heterocyclic Amines |journal=Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis |date=1997 |volume=376 |issue=1–2 |page=37-41 |doi=10.1016/S0027-5107(97)00023-7 |url=https://www.sciencedirect.com/science/article/pii/S0027510797000237}}</ref> 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.<ref>Felton, JS., et al. (1994) Effect of microwave pretreatment on heterocyclic aromatic amine mutagens/carcinogens in fried beef patties. ]. 158:59-68.</ref>
			{| class="wikitable"
			|+ PhIP values for cooked meat<ref>Norrish, A.E., Ferguson, L.R., Knize, M.G., Felton, J.S., Sharpe, S.J., Jackson, R.T., 1999. Heterocyclic amine content of cooked meat and risk of prostate cancer. J. Natl. Cancer Inst. 91, 2038–2044.</ref>
			|-
			! Meat type !! Cooking variation !! PhIP ng/g ± SD
			|-
			| rowspan="3"| Beef (1.5&nbsp;cm thick) || Fried - medium rare (51&nbsp;°C) || 0.29 ± 0.14
			|-
			| Fried - well-done (63&nbsp;°C) || 0.73 ± 0.02
			|-
			| Fried - very well-done (74&nbsp;°C) || 7.33 ± 0.11
			|-
			| rowspan="2"| Lamb chop || Fried - medium (75&nbsp;°C) || 0
			|-
			| Fried - well-done (85&nbsp;°C) || 2.4
			|-
			| rowspan="2"| Pork (2&nbsp;cm thick) || Fried - medium (63&nbsp;°C) || 0.37 ± 0.06
			|-
			| Fried - well-done (83&nbsp;°C) || 7.82 ± 1.13
			|-
			| rowspan="2"| Mince beef patty (2&nbsp;cm thick) || Fried - medium (51&nbsp;°C) || 0
			|-
			| Fried - well-done (58&nbsp;°C) || 3.96 ± 0.13
			|-
			| rowspan="2"| Chicken (2.5&nbsp;cm, no skin) || Fried - lightly browned (63&nbsp;°C) || 0.2 ± 0.005
			|-
			| Fried - well-done (79&nbsp;°C) || 17.54 ± 0.17
			|-
			| rowspan="2"| Sausage || Fried - lightly browned (42&nbsp;°C) || 0
			|-
			| Fried - well browned (70&nbsp;°C) || 0.61 ± 0.06
			|-
			| rowspan="2"| Bacon, middle || Fried - lightly cooked || 0.11 ± 0.002
			|-
			| Fried - well cooked || 1.93 ± 0.37
			|}
			== 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.<ref>Sinha, R., et al. (1995) High concentrations of the carcinogen 2-amino-1-methyl-6-phenylimidazopyridine (PhIP) occur in chicken but are dependent on the cooking method. Cancer Res. 55:4516-4519.</ref><ref>Sinha, R., et al. (1998) Heterocyclic amine content in beef cooked by different methods to varying degrees of doneness and gravy made from meat drippings. Food Chem Toxicol. 36:279-287.</ref><ref>Sinha, R., et al. (1998) Heterocyclic amine content of pork products cooked by different methods and to varying degrees of doneness. Food Chem Toxicol. 36:289-297.</ref><ref>Knize, MG., et al. (1995) Heterocyclic amine content in fast-food meat products. Food Chem Toxicol 33:545-551.</ref> Another method directly measures the quantity of PhIP in a cooked meat sample.<ref>Keating, G., et al. (1999) Factors determining dietary intakes of heterocclic amines in cooked foods. Mutation Research 443:149-156.</ref> 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.<ref>Sinha, R., et al. (2001). Dietary Intake of ], meat-derived Mutagenic Activity, and Risk of Colorectal Adenomas. Cancer Epidemiol Biomarkers Prev. 10:559-562.</ref> Direct measurement methods have determined dietary intake levels of PhIP to range from 0.07-4.3&nbsp;ng/kg per day.
			== Metabolism ==
			Metabolic activation is required for PhIP to function as a ]. 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 ] enzyme N-oxidation by Cytochrome P-450 1A2 (]). PhIP can be further metabolized into a more potent metabolite through O-acetylation by hepatic or colonic ] 1 (NAT1) and ] (NAT2), or by sulfotransferases. However, PhIP may also undergo a detoxification pathway through ] conjugation reaction via UDP-]s (UGTs) to form N-glucuronide conjugates.<ref name="cross" /> PhIP's nitrenium ion intermediate is a powerful ] that has propensity to form C-8 ] ] with the ].<ref name="felton1">Felton, J., et al. (1997). Health Risks of ]. Mutation Research. 376: 37-41.</ref> 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.<ref>Schweikl, H., et al (1993) Expression of CYP1A1 and ] genes in human liver. Pharmacogenetics. 3:239 -249.</ref> 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.<ref>Roberts-Thompson, I., et al. (1996)Diet, acetylator ], and risk of colorectal neoplasia. Lancet. 347:1372-1374.</ref> Individuals with the rapid ] 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.<ref>{{cite journal|last=Japanese Journal of Cancer Research|title=Dose-dependent Induction of Mammary Carcinomas in Female Sprague-Dawley Rats with 2-Amino-1-methyl-6-phenylimidazopyridine|journal=Japanese Journal of Cancer Research|volume=87|issue=11|pages=1116–1120|doi=10.1111/j.1349-7006.1996.tb03120.x|year=1996|pmid=9045939 |pmc=5921009}}</ref> An '']'' study found mice injected with 5, 10, 12, 18, 20, 24, 28, 32, or 36&nbsp;mg/kg bw showed a strong correlation between consumption of PhIP and genetic damage.<ref>Durling, L., et al. (2005) A comparison of genotoxicity between three common ] and acrylamide. Mutat. Res. 580:103-110.</ref>
			== Risk assessments for PhIP ==
			There is no dose without 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.<ref>Benford, D., et al (2009) Application of the Margin of Exposure (MOE) approach to substances in food that are genotoxic and carcinogenic*. ''Food and Chemical Toxicology''. 48 S2-S24.</ref>
			{| class="wikitable" border="1"
			|+ Calculated MOE for prostate carcinoma based on dietary exposure to PhIP from cooked meats
			! Exposure estimate (mg/kg-bw/day)!! MOE for model average BMDL <sub>10</sub>
			|-
			| Average (50%) (0.000006) || 100,000
			|-
			| High Level (0.00002)|| 40,000
			|}
			{| class="wikitable" border="1"
			|+ Calculated MOE for mammary carcinoma based on dietary exposure to PhIP from cooked meats
			! Exposure estimate (mg/kg-bw/day)!! MOE for model average BMDL <sub>10</sub>
			|-
			| Average (50%) (0.000006) || 80,000
			|-
			| High Level (0.00002)|| 20,000
			|}
			== 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 (]) test and induced chromosomal abnormalities in human and Chinese hamster cells ]. PhIP has also formed ] ] ] in both rats and monkeys.<ref name="carthew">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-penylimidazopyridine). Food and Chemical Toxicology. 48: S98-S105.</ref> PhIP has been tested for carcinogenicity in both mice and rats by oral administration. Increases in ] were seen in mice and increases in ] of the small and large intestine in males and mammary ] in female were seen in rats.<ref name="carthew"/> Also, an increasing number of ] 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.<ref>Zheng, W. & Lee, S. (2009). Well-done meat intake, heterocyclic amine exposure, and cancer risk. Nutr Cancer. 61(4):437-446.</ref>
			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.<ref>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-phenylimidazopyridine. Cancer Epidemiol Biomarkers Prev. 8:507-512.</ref>
			== References ==
			{{reflist}}
			{{DEFAULTSORT:Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, 2-}}
			]