A new colon and mammary carcinogen in cooked food, 2-amino-1-methyl-6-phenylimidazo[4,5-<i>b</i>]pyridine (PhIP)

Ito, Nobuyuki; Hasegawa, Ryohei; Sano, Masashi; Tamano, Seiko; Esumi, Hiroyasu; Takayama, Seiji; Sügimura, Takashi

doi:10.1093/carcin/12.8.1503

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“…A predominant HA found in cooked and particularly in welldone chicken and beef is 2 -amino-1-methyl -6-phenylimidazo [ 4,5-b] pyridine ( PhIP ) (Felton et al, 1984(Felton et al, , 1986Felton and Knize, 1990a,b;Sinha et al, 1995 ). Dietary exposure to PhIP has been shown to induce colon, intestinal and mammary adenocarcinomas in rats Ochiai et al, 1991;Ito et al, 1991Ito et al, , 1997Ghoshal et al, 1994 ), as well as prostate cancer (PC ) in rats (Shirai et al, ,1999. Another predominant HA found in cooked meats, 2 -amino-3,8-dimethylimidazo [ 4,5-f] quinoxaline (MeIQx), causes tumors at multiple sites in rats and mice Bogen, 1994 ).…”

Section: Introductionmentioning

confidence: 99%

U.S. dietary exposures to heterocyclic amines*

Bogen

Keating

2001

J Expo Sci Environ Epidemiol

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Heterocyclic amines ( HAs ) formed in fried, broiled or grilled meats are potent mutagens that increase rates of colon, mammary, prostate and other cancers in bioassay rodents. Studies of how human dietary HA exposures may affect cancer risks have so far relied on fairly crudely defined HA -exposure categories. Recently, an integrated, quantitative approach to HA -exposure assessment ( HAEA ) was developed to estimate compound -specific intakes for particular individuals based on corresponding HA -concentration estimates that reflect their meat -type, intake -rate, cooking -method and meat -doneness preferences. This method was applied in the present study to U.S. national Continuing Survey of Food Intakes by Individuals ( CSFII ) data on meats consumed and cooking methods used by > 25,000 people, after adjusting for underreported energy intake and conditional on meat -doneness preferences estimated from additional survey data. The U.S. population average lifetime time -weighted average of total HAs consumed was estimated to be $9 ng / kg / day, with 2 -amino -1 -methyl -6 -phenylimidazo [ 4,5 -b ] pyridine ( PhIP ) estimated to comprise about two thirds of this intake. Pan -fried meats were the largest source of HA in the diet and chicken the largest source of HAs among different meat types. Estimated total HA intakes by male vs. female children were generally similar, with those by ( 0 -to 15 -year -old ) children $25% greater than those by ( 16 + -year -old ) adults. Race -, age -and sex -specific mean HA intakes were estimated to be greatest for African American males, who were estimated to consume $2 -and $3 -fold more PhIP than white males at ages < 16 and 30 + years, respectively, after considering a relatively greater preference for more well -done items among African Americans based on national survey data. This difference in PhIP intakes may at least partly explain why prostate cancer ( PC ) kills $2 -fold more African American than white men, in view of experimental data indicating that PhIP mutates prostate DNA and causes prostate tumors in rats. Journal of Exposure Analysis and Environmental Epidemiology ( 2001 ) 11, 155 ± 168.

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Section: Introductionmentioning

confidence: 99%

U.S. dietary exposures to heterocyclic amines*

Bogen

Keating

2001

J Expo Sci Environ Epidemiol

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“…11 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) is an environmentally abundant HCA, produced by pyrolysis of amino acids and proteins during cooking of meat and fish. 6 It is also contained in beer, wine and cigarette smoke condensate 12,13 and has been shown to induce cancers of the colon, breast 14 and prostate. 15 PhIP is found at a concentration range of 0.56-69.2 ng/g in cooked foods and daily intake is estimated to be 0.1-13.8 mg/person.…”

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Lack of large intestinal carcinogenicity of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine at low doses in rats initiated with azoxymethane

Doi

Wanibuchi

Salim

et al. 2005

Intl Journal of Cancer

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2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), an abundant food-derived heterocyclic amine (HCA), has attracted particular attention as a human colon carcinogen. Humans are in fact exposed to continuous low doses of HCAs during lifetime. Therefore, we focused on rat large intestinal carcinogenicity of PhIP at levels that mimic practical human exposure. A total of 192 6-weekold male F344 rats were subcutaneously injected twice with 15 mg/ kg body weight azoxymethane (AOM), then continuously fed various doses (0, 0.001, 0.01, 0.1, 1, 10, 50 and 200 ppm) of PhIP in the diet. At week 16, aberrant crypt foci (ACF) were quantitatively analyzed. At week 36, tumor occurrence was pathologically analyzed. Then immunohistochemical examinations were performed. PhIP was found to enhance strongly AOM-initiated rat large intestinal tumorigenesis at high doses (50 and 200 ppm), while lower doses (0.001-10 ppm) had no apparent effects. High doses also caused variation in tumor histologic types and their distribution throughout the large intestinal segments. Frequencies of ACF/cm 2 did not meaningfully vary between the groups. Cellular proliferation activity in normal-appearing colonic mucosa was significantly increased at high doses. These novel findings may provide evidence of a low-dose potential for PhIP, with a no-observed effect level speculated to be 10 ppm in the present initiation-promotion experimental model. ' 2005 Wiley-Liss, Inc.Key words: rat; large intestine; carcinogenesis; PhIP; azoxymethane; no-observed effect level Carcinogenesis is widely accepted to be a multistep process caused by a series of genetic and/or subsequent epigenetic alterations that are indispensable to the different stages from initiation to promotion and progression of cancer development. 1,2 Humans are consistently exposed to very many naturally occurring or synthetic chemical carcinogens at quite low-dose levels in the environment, 3 although concomitantly they may consume mixtures of naturally occurring anticarcinogenic compounds in their daily diets. 4 One focus of attention has been food-derived heterocyclic amines (HCAs) generated in cooking processes that have proved to be carcinogenic in rodent species. 5,6 HCAs are highly mutagenic 6 and genotoxic carcinogens that are generally thought to have no threshold in exerting their carcinogenic potential, which was postulated to exhibit dose dependence in vivo. 3 However, in practice, low-dose administration has not necessarily led to cancer development in the rat liver. 7 Thereby, in our laboratory, the nonthreshold theory for hepatocarcinogenesis of one HCA, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), has been challenged, since in vivo dose-response curves do not show linearity at low-dose levels. 8,9 Moreover, thresholds for chemical carcinogenesis were concluded in a recent article. 10 In practice, the many factors active in vivo, from intake of carcinogens through to lesion development, mean that the processes are highly complicated, so that if the DNA-damaging pote...

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“…32,33 A recent report by Sinha and colleagues 34 indicated that PhIP could be one of the causative agents for colon carcinogenesis in humans. To elucidate the biological significance of ACF in colon carcinogenesis, ACF induced in F344 male rats by PhIP were subjected to morphological and genetic analyses.…”

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Characterization of Dysplastic Aberrant Crypt Foci in the Rat Colon Induced by 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine

Ochiai¹,

Ushigome

Fujiwara³

et al. 2003

The American Journal of Pathology

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The multistage model of colon carcinogenesis is well established in both humans and experimental animals, and aberrant crypt foci (ACF) are generally assumed to be putative preneoplastic lesions of the colon. However, morphological analyses of ACF have suggested that they are highly heterogeneous in nature and their role in tumorigenesis is still controversial. To better understand the biological significance of ACF in carcinogenesis, morphological and genetic analyses were performed using a rat colon cancer model induced by a food-borne colon carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). ACF of different sizes were collected at weeks 6, 18, 25, and 32 after three cycles of 2-week PhIP feeding (400 ppm in diet) with 4-week intervals on a high-fat diet, and a total of 110 ACF, representing approximately three-quarters of the total ACF, were subjected to histological evaluation. Thirty (27%) were diagnosed as dysplastic ACF, based on cytological and structural abnormalities of crypts. Dysplastic ACF were detected even at week 6 (0.4 per rat), and the numbers increased slightly at later time points, being 0.8, 1.4, and 0.8 per rat at weeks 18, 25, and 32, respectively. The sizes of these dysplastic ACF varied widely from 1 to 16 crypts and 50% (15 of 30) were composed of less than 4 crypts. Immunohistochemical analysis revealed that 83% (25 of 30) of dysplastic ACF demonstrated ␤-catenin accumulation; 22 only in the cytoplasm and 3 in both the cytoplasm and nucleus, the latter manifesting a higher grade of dysplasia as compared with the former. Seven dysplastic ACF harbored ␤-catenin mutations at codon 32, 34, or 36 in exon 2, and one had an Apc mutation at the boundary of intron 10 and exon 11. Mutations at these sites were also commonly found in colon tumors induced by PhIP. The results of our present study indicate that dysplastic ACF, which accounted for approximately one-fourth of the total ACF, are preneoplastic lesions of colon cancers induced by PhIP in rats.

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A new colon and mammary carcinogen in cooked food, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)

Cited by 541 publications

References 0 publications

U.S. dietary exposures to heterocyclic amines*

U.S. dietary exposures to heterocyclic amines*

Lack of large intestinal carcinogenicity of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine at low doses in rats initiated with azoxymethane

Characterization of Dysplastic Aberrant Crypt Foci in the Rat Colon Induced by 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine

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