Cancer Letters

Cancer Letters

Volume 194, Issue 1, 8 May 2003, Pages 25-35
Cancer Letters

Mechanistic approach of contrasting modifying effects of caffeine on carcinogenesis in the rat colon and mammary gland induced with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

https://doi.org/10.1016/S0304-3835(03)00051-XGet rights and content

Abstract

Caffeine exerts potent chemopreventive action against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced rat mammary gland carcinogenesis, but acts as a co-carcinogen in the colon. The present work was performed to clarify mechanisms underling these organ dependent actions. Female F344 rats were given PhIP and caffeine, PhIP alone, caffeine alone or no treatment for 4 weeks. PhIP-DNA adduct formation in the colon was significantly higher in the PhIP+caffeine than in the PhIP group, but levels in the mammary glands showed no inter-group differences. CYP1A2 mRNA expression in the livers of the PhIP+caffeine group tended to be higher than in either the PhIP or the caffeine alone groups. High mRNA expression for both N-acetyltransferase (NAT) 1 and NAT2 was observed in the colon, with less expression in the mammary gland. The levels of four DNA-repair enzymes were not influenced by the caffeine treatment. In conclusion, only increased level of DNA adducts in the colon partially related to the modifying effects of caffeine on PhIP-induced rat carcinogenesis. Thus, other unknown factors must be contributory.

Introduction

Since Sugimura and co-workers’ first found that many highly mutagenic compounds, named heterocyclic amines (HCAs), are produced during cooking of meats and fish [1], ten HCAs have been shown to induce malignant tumors in rats and/or mice, some also being carcinogenic in primates [2]. Among them, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is most abundant HCA in cooked food, and confirmed to be present in human urine [3], [4], [5], [6]. In our laboratory, PhIP has been demonstrated to induce mammary, colon and prostate carcinomas in rats [7], [8], [9]. These target organs correspond with the major three organs in which malignant tumors are most common in Western countries, where consumption of meat is high. Thus, PhIP may play an important role in cancer development in man.

PhIP, like many carcinogens, requires metabolic activation in order to exert its genotoxicity and this is highly dependent upon cytochrome P450 (CYP) 1A2 to be N-hydroxy-PhIP [10], [11]. Further metabolism is through O-acetylation, catalyzed by N-acetyltransferase (NAT), but the N-acetoxy ester derivative form is unstable and spontaneously converted to a reactive electrophilic arylnitrenium ion. This ultimate metabolite is able to bind covalently to DNA and form adducts that may cause mutations and lead to induction of cancer [12]. It is thus possible that chemicals influencing induction of phase I or II enzymes can modulate PhIP-induced carcinogenesis.

Caffeine, one of the most commonly consumed compounds contained in many drinks, especially coffee and tea, is known to have a broad range of biochemical and physiological activities [13]. Several reports have documented effects of caffeine on carcinogenesis at various organ sites. Inhibition has been shown in the lung of rats and mice treated with a nicotine-derived carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [14], [15], in the skin of mice exposed to ultraviolet light [16] and in the stomach of rats given N-methyl-N′-nitro-N-nitrosoguanidine and sodium chloride [17]. However, with initiation/promotion protocols using mammary gland specific carcinogens such as N-methyl-N-nitrosourea and dimethylbenz(a)anthracene, no inhibition was apparent [18], [19]. Since caffeine is also a hepatic CYP1A2 inducer in rats [20], it would be expected to modify PhIP metabolism and carcinogenesis. In the Ames test and a micronucleus assay with Hep-G2 cells, caffeine was found to inhibit PhIP-induced mutagenesis [21], [22]. In contrast, co-administration of caffeine and PhIP to F344 rats resulted in a significant increase of colonic aberrant crypt foci and CYP1A2 expression [23]. Interestingly, in our previous study, the simultaneous administration of PhIP and caffeine to female F344 rats for 54 weeks resulted in significant reduction of mammary gland tumor formation but colon carcinogenesis was clearly enhanced [24]. This contradictory result regarding caffeine modification of carcinogenesis may have implications with respect to human disease, because of the possible exposure to both caffeine and PhIP on a daily basis.

In the present study, in an attempt to elucidate the reasons why caffeine acts differently in the mammary glands and colon of PhIP-treated rats, we investigated its influence on PhIP-DNA adduct formation, cell proliferation, apoptosis and the expression of relevant metabolic enzymes, as well as examples involved in DNA repair.

Section snippets

Chemicals and animals

PhIP hydrochloride was obtained from the NARD Institute (Osaka, Japan) and caffeine anhydrous from Wako Pure Chemical Industries (Osaka, Japan). A total of 25 female F344 rats, 5-week-old, were purchased from Charles River Japan (Atsugi, Japan) and housed three or four to a plastic cage on hard-wood chips, in an air-conditioned room at 22±2 °C and 50% humidity with a 12/12 h light/dark cycle. They were given commercial pellet basal diet (Oriental MF; Oriental Yeast, Tokyo, Japan) and tap water

Results

The final body weights in the group treated with PhIP alone were significantly lower than those in the non-PhIP treated group (Table 1). The relative liver weights of rats treated caffeine were higher than the non-caffeine treated group values. The relative uterus weights were not significantly affected by PhIP and/or caffeine treatment. Serum levels of estrogen showed no apparent inter-group differences (data not shown).

Histological examination did not show evidence of hyperproliferation,

Discussion

PhIP is a carcinogenic heterocyclic amine to which man may be exposed through the daily diet [1], [3], [6]. Significant is the fact that it induces three major malignancies, cancers of the breast, colon and prostate in rats [7], [9], pointing to a role as a human carcinogen. Preventing PhIP carcinogenicity may therefore be an important issue for human health.

In the present study an increase of PhIP-DNA adduct formation with caffeine treatment was noted in the colon mucosa but without any change

Acknowledgements

This work was supported in part by Grants-Aid for Cancer Research from the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare, a Grant-in-aid from the Ministry of Health, Labour and Welfare for the Second Term Comprehensive 10-Year Strategy for Cancer Control, Japan, and a grant from the Society for Promotion of Toxicological Pathology of Nagoya, Japan.

References (48)

  • M Nagao et al.

    Mutagenicities of smoke condensates and the charred surface of fish and meat

    Cancer Lett.

    (1977)
  • K Wakabayashi et al.

    Food-derived mutagens and carcinogens

    Cancer Res.

    (1992)
  • J.S Felton et al.

    The isolation and identification of a new mutagen from fried ground beef: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)

    Carcinogenesis

    (1986)
  • H Ushiyama et al.

    Presence of carcinogenic heterocyclic amines in urine of healthy volunteers eating normal diet, but not of inpatients receiving parenteral alimentation

    Carcinogenesis

    (1991)
  • K Wakabayashi et al.

    Exposure to heterocyclic amines

    Environ. Health Perspect.

    (1993)
  • D.W Layton et al.

    Cancer risk of heterocyclic amines in cooked foods: an analysis and implications for research

    Carcinogenesis

    (1995)
  • N Ito et al.

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

    Carcinogenesis

    (1991)
  • R Hasegawa et al.

    Dose-dependence of 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP) carcinogenicity in rats

    Carcinogenesis

    (1993)
  • T Shirai et al.

    The prostate: a target for carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) derived from cooked foods

    Cancer Res.

    (1997)
  • J.A Holme et al.

    Genotoxicity of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP): formation of 2-hydroxamino-PhIP, a directly acting genotoxic metabolite

    Carcinogenesis

    (1989)
  • H Wallin et al.

    Differential rates of metabolic activation and detoxication of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by different cytochrome P450 enzymes

    Carcinogenesis

    (1990)
  • H.A Schut et al.

    DNA adducts of heterocyclic amine food mutagens: implications for mutagenesis and carcinogenesis

    Carcinogenesis

    (1999)
  • IARC, Coffee, Tea, Mate, Methylxanthines, and Methylglyoxal, IARC Monographs on the Evaluation of Carcinogenic Risk to...
  • F.L Chung et al.

    Inhibition of lung carcinogenesis by black tea in Fischer rats treated with a tobacco-specific carcinogen: caffeine as an important constituent

    Cancer Res.

    (1998)
  • F.L Chung

    The prevention of lung cancer induced by a tobacco-specific carcinogen in rodents by green and black tea

    Proc. Soc. Exp. Biol. Med.

    (1999)
  • Y.P Lu et al.

    Inhibitory effects of orally administered green tea, black tea, and caffeine on skin carcinogenesis in mice previously treated with ultraviolet B light (high-risk mice): relationship to decreased tissue fat

    Cancer Res.

    (2001)
  • A Nishikawa et al.

    Effects of caffeine on glandular stomach carcinogenesis induced in rats by N-methyl-N′-nitro-N-nitrosoguanidine and sodium chloride

    Food Chem. Toxicol.

    (1995)
  • K El-Bayoumy

    Evaluation of chemopreventive agents against breast cancer and proposed strategies for future clinical intervention trials

    Carcinogenesis

    (1994)
  • L.C VanderPloeg et al.

    Influence of caffeine on development of benign and carcinomatous mammary gland tumors in female rats treated with the carcinogens 7,12-dimethylbenz(a)anthracene and N-methyl-N-nitrosourea

    Cancer Res.

    (1991)
  • L Chen et al.

    Caffeine induces cytochrome P4501A2: induction of CYP1A2 by tea in rats

    Drug Metab. Dispos.

    (1996)
  • J.H Weisburger et al.

    Inhibition of PhIP mutagenicity by caffeine, lycopene, daidzein, and genistein

    Mutat. Res.

    (1998)
  • R Sanyal et al.

    Inhibition of the genotoxic effects of heterocyclic amines in human derived hepatoma cells by dietary bioantimutagens

    Mutagenesis

    (1997)
  • H Tsuda et al.

    Heterocyclic amine mixture carcinogenesis and its enhancement by caffeine in F344 rats

    Cancer Lett.

    (1999)
  • A Hagiwara et al.

    Organ-dependent modifying effects of caffeine, and two naturally occurring antioxidants α-tocopherol and n-tritriacontane-16,18-dione, on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary and colonic carcinogenesis in female F344 rats

    Jpn. J. Cancer Res.

    (1999)
  • Cited by (0)

    View full text