DNA adducts of heterocyclic amines: formation, removal and inhibition by dietary components

Schut, Herman A.J.; Cummings, David A.; Smale, Maarten H.E.; Josyula, Shylaja; Friesen, Marlin D.

doi:10.1016/s0027-5107(97)00042-0

Cited by 41 publications

(16 citation statements)

References 36 publications

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“…The rates of repair of PhIP-DNA adducts in liver and colon (Figs. 4C,D, 5C,D) are relatively slow when compared to those observed after a single oral bolus (50 mg/kg) of PhIP [35], and confirm similar results reported previously [50].…”

Section: Discussionsupporting

confidence: 91%

“…It is active against both indirect-and direct-acting carcinogens [28] as well as a variety of experimental tumors, regardless of the carcinogenic agent used [25][26][27][28][29][30][31]; it modulates both phase I and phase II enzymes involved in carcinogen metabolism [42][43][44][45][46][47]49]; and it is active at low dietary concentrations [48][49][50]. When given only during the post-initiation phase of experimental carcinogenesis, however, I3C promotes tumor formation in certain systems [51,52].…”

Section: Discussionmentioning

confidence: 99%

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Chemopreventive properties of Indole-3-Carbinol (I3C): Inhibition of DNA adduct formation of the dietary carcinogen, 2-Amino-1-Methyl-6-Phenylimidazo [4,5-b]Pyridine (PhIP), in female F344 rats

He¹,

Smale²,

Schut³

1997

J. Cell. Biochem.

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Indole-3-carbinol (I3C), a naturally occurring inhibitor of experimental carcinogenesis, was evaluated for its possible inhibitory effect on DNA-adduct formation of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), a dietary mutagen, in female F344 rats. PhIP is a mammary carcinogen in female F344 rats and a colon carcinogen in male F344 rats. Four-week-old animals (4/group) were maintained on powdered AIN-76A diet with or without I3C (0.02% or 0.1%, w/w) for 58 days. PhIP (0.04%, w/w) was added to the diet from days 15 through 42. Animals were killed on days 43 and 58. DNA isolated from mammary epithelial cells (MECs), colon, liver, and white blood cells (WBCs) was analyzed for PhIP-DNA adducts by 32 P-postlabeling assays. On day 43, adduct levels of the group receiving 0.1% dietary I3C decreased in MECs (91.9%), colon (67.2%), liver (69.2%), and WBCs (82.3%). On day 58, DNA adduct formation was inhibited in the colon (81.3-82.2%) at both dietary I3C concentrations, and in liver (46.8%) only in the animals fed 0.1% I3C. When incorporated in the diet after exposure to dietary PhIP (0.04% for 2 weeks), I3C (0.1%) had no effect on the rate of removal of PhIP-DNA adducts over the next 28 days. It is concluded that dietary I3C inhibits PhIP-DNA adduct formation in the female F344 rat but does not affect adduct removal. I3C may be a promising chemopreventive agent in PhIP-induced carcinogenesis in rats.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Chemopreventive properties of Indole-3-Carbinol (I3C): Inhibition of DNA adduct formation of the dietary carcinogen, 2-Amino-1-Methyl-6-Phenylimidazo [4,5-b]Pyridine (PhIP), in female F344 rats

He¹,

Smale²,

Schut³

1997

J. Cell. Biochem.

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“…In contrast, male F344 rats were more susceptible than females to hepatocarcinogenesis by IQ, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-6-methyl-dipyrido[1,2-a:3Ј,2Ј-d]imidazole (Glu-P-1), and 2-aminodipyrido[1,2-a:3Ј,2Ј-d]imidazole (Glu-P-2). In addition, higher PhIP-DNA adduct levels were detected in the tissues of male rats than in those of female rats after repeated daily dosing with PhIP [Schut et al, 1997;Schut and Yao 2000]; DNA adducts resulting from treatment by MeIQ were also found to be higher in male rats than in female rats in several tissues, including the liver, kidney, and white blood cells [Thorgeirsson et al, 1995]. Therefore, it is not surprising to see that the PhIP-induced MF in the kidney of male rats is almost twice as high as that in the female rats.…”

Section: Discussionmentioning

confidence: 93%

Sex‐specific induction of mutations by PhIP in the kidney of male and female rats and its modulation by conjugated linoleic acid

Yang

Glickman

Boer

2002

Environ and Mol Mutagen

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The heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a recognized mutagen and carcinogen in the colon and prostate of male rats and in the mammary gland of female rats. In the current study, we examined the mutagenicity of PhIP in the kidney of male and female lacI transgenic rats and its modulation by a dietary chemopreventive agent, conjugated linoleic acid (CLA). Sex-specific changes in mutation were observed following PhIP and CLA treatment. Exposure to 100 ppm PhIP through dietary supplementation for 47 days induced a lacI mutation frequency (MF) of 7.7 +/- 0.3 x 10(-5) and 4.7 +/- 1.0 x 10(-5) in the kidney of male and female rats, respectively. The PhIP-induced MFs in the kidney of male and female rats were significantly different from each other and were 300% (P < 0.001) and 60% (P < 0.05) higher than the corresponding controls, respectively. When rats were given CLA along with PhIP, CLA completely inhibited the formation of PhIP-induced mutations in the kidney of female rats, but not in male rats. Comparison of mutational spectra did not detect significant differences between male rats treated with PhIP and PhIP + CLA. However, unlike the -1 frameshifts induced by PhIP in the colon and prostate, which consist primarily of G:C deletions, -1 frameshifts in the kidney involved the loss of both G:C and A:T basepairs. Our data indicate that the kidney of the rats responds in a sex-dependent way to mutagenesis and antimutagenesis by PhIP and CLA. These differences may be related to hormonally regulated induction of P450 enzymes or cell proliferation.

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“…Although linoleic acid enhances mammary carcinogenesis, conjugated linoleic acid (CLA), fed both during and after or solely following carcinogen exposure, has been demonstrated to inhibit tumorigenesis induced by DMBA or MNU [Ip et al, 1994], and to suppress PhIP-DNA adduct formation in rat mammary glands [Schut et al, 1997]. In the present experiment, we measured proliferating cell nuclear antigen (PCNA) labeling indices of tumor cells in animals given CFA-S or CFA-P after PhIP initiation and observed a clear decrease compared with PhIP-alone values (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Chemoprevention of heterocyclic amine‐induced mammary carcinogenesis in rats

Hirose

Nishikawa

Shibutani

et al. 2002

Environ and Mol Mutagen

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2-Amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) is one of the most prevalent carcinogenic heterocyclic amines in the environment, targeting the colon, prostate, pancreas, and mammary gland in rodents. Chemopreventive effects of synthetic and naturally occurring compounds on PhIPinduced rat mammary carcinogenesis were investigated in a series of experiments. In a PhIP feeding model, groups of 20 -21 female F344 rats each, were treated with 0.02% PhIP alone or PhIP plus 0.5% 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), 1% green tea catechins, 1% ␣-tocopherol, 0.1% ellagic acid, or 1% chlorophyllin, each in the diet, or 0.1% caffeine in drinking water for 52 weeks. To assess the mechanism of HTHQ and caffeine inhibition of PhIP-induced carcinogenesis, effects of these compound on the in vitro metabolic activation of PhIP were examined in the presence of S9 mix. In the next series of experiments, the PhIP intragastric dose model was applied to allow separate investigation of the effects of chemicals during the initiation and postinitiation periods. In these experiments, female Sprague-Dawley rats were given eight intragastric doses of 100 mg/kg body weight during the first 4 -8 weeks for initiation. Either during initiation or after initiation, or only after initiation, animals were treated with either corn or perilla oil at doses of 5 and 20%, conjugated fatty acid derived from safflower oil (CFA-S) or perilla oil (CFA-P) at a dose of 1%, arctiin at doses of 0.02 and 0.2% in the diet, or sodium nitrite (NaNO 2 ) at a dose of 0.2% in drinking water. In the PhIP feeding model, administration of PhIP alone for 52 weeks induced adenocarcinomas in 40% of rats, but the incidence was remarkably reduced to 5% by the simultaneous treatment with 0.5% HTHQ, a strong lipophilic phenolic antioxidant, or to 10% by 0.1% caffeine. Administration of 1% chlorophyllin exerted similar, albeit weaker, effects. ␣-Tocopherol at a dose of 0.5% only reduced the multiplicity of carcinomas, and 1% green tea catechins only the mean size of mammary tumors. In a metabolic activation study of PhIP, HTHQ and caffeine clearly inhibited the formation of metabolites. In the PhIP gastric dose model, among the naturally occurring compounds examined, a plant lignan arctiin, perilla oil, which contains a large amount of n-6 ␣-linolenic acid, and CFA-S or CFA-P inhibited mammary tumor development, particularly in the postinitiation period, although a clear dose response was not observed. Treatment with 0.2% NaNO 2 in the initiation period was found to lower the volume of mammary tumors. The present results indicate that a number of compounds may be candidate chemopreventive agents against PhIP-induced mammary carcinogenesis, acting through different mechanisms and depending on the stage of carcinogenesis. Environ. Mol. Mutagen. 39:271-278, 2002.

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DNA adducts of heterocyclic amines: formation, removal and inhibition by dietary components

Cited by 41 publications

References 36 publications

Chemopreventive properties of Indole-3-Carbinol (I3C): Inhibition of DNA adduct formation of the dietary carcinogen, 2-Amino-1-Methyl-6-Phenylimidazo [4,5-b]Pyridine (PhIP), in female F344 rats

Chemopreventive properties of Indole-3-Carbinol (I3C): Inhibition of DNA adduct formation of the dietary carcinogen, 2-Amino-1-Methyl-6-Phenylimidazo [4,5-b]Pyridine (PhIP), in female F344 rats

Sex‐specific induction of mutations by PhIP in the kidney of male and female rats and its modulation by conjugated linoleic acid

Chemoprevention of heterocyclic amine‐induced mammary carcinogenesis in rats

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