Contrasting effects of acute and chronic dietary exposure to 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) on xenobiotic metabolising enzymes in the male Fischer 344 Rat: implications for chemoprevention studies

McPherson, Rachel A. C.; Tingle, Malcolm D.; Ferguson, Lynnette R.

doi:10.1007/pl00007384

Cited by 9 publications

(8 citation statements)

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“…In a study by McPherson et al. ( 47 ) , no significant induction in mRNA expression level or activity of either CYP1A1 or CYP1A2 were reported in the livers of rats receiving 300 p.p.m. IQ in the diet for 52 weeks, but these enzymes were significantly increased after daily administration of 20 mg/kg b.w.…”

Section: Discussionmentioning

confidence: 91%

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Low‐dose carcinogenicity of 2‐amino‐3‐methylimidazo[4,5‐f ]quinoline in rats: Evidence for the existence of no‐effect levels and a mechanism involving p21^{Cip / WAF1}

Wei¹,

Wanibuchi²,

Nakae³

et al. 2010

Cancer Science

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The carcinogenicity of the low amounts of genotoxic carcinogens present in food is of pressing concern. The purpose of the present study was to determine the carcinogenicity of low doses of the dietary genotoxic carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and to investigate mechanisms by which IQ exerts its carcinogenic effects. A total of 1595 male F344 rats were divided into seven groups and administered with IQ at doses of 0, 0.001, 0.01, 0.1, 1, 10 and 100 p.p.m. in the diet for 16 weeks. We found that IQ doses of 1 p.p.m. and below did not induce preneoplastic lesions in either the liver or the colon, while IQ doses of 10 and 100 p.p.m. induced preneoplastic lesions in both of these organs. These results demonstrate the presence of no-effect levels of IQ for both liver and colon carcinogenicity in rats. The finding that p21Cip ⁄ WAF1 was significantly induced in the liver at doses well below those required for IQ mediated carcinogenic effects suggests that induction of p21Cip ⁄ WAF1 is one of the mechanisms responsible for the observed no-effect of low doses of IQ. Furthermore, IQ administration caused significant induction of CYP1A2 at doses of 0.01-10 p.p.m., but administration of 100 p.p.m. IQ induced CYP1A1 rather than CYP1A2. This result indicates the importance of dosage when interpreting data on the carcinogenicity and metabolic activation of IQ. Overall, our results suggest the existence of no-effect levels for the carcinogenicity of this genotoxic compound. (Cancer Sci 2011; 102: 88-94) E xposure to environmental carcinogens is one of the most significant causes of human cancers. Determination of the dose-response relationship between carcinogen exposure and induction of cancer is one of the most important areas of chemical risk assessment. Of particularly high priority is the cancer risk assessment of dietary carcinogens.Heterocyclic amines (HCA) are well known dietary genotoxic carcinogens derived from cooked protein-rich foods such as meat and fish, (1)(2)(3) and the carcinogenicities of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) have been widely investigated in various animal models. MeIQx induces cancers of the liver, zymbal gland, skin and clitoral gland in rats, (4) and caners of the liver and lung, and lymphoma and leukemia in mice.(5) PhIP induces colon cancers and mammary gland cancers in rats, (6) and lymphomas in mice.(7) IQ induces cancers of the liver, colon, mammary and zymbal glands in rats, caners of the liver, lung and forestomach in mice, and cancer of the liver in nonhuman primates.(8-10) MeIQx and PhIP are classified as category 2B compounds (possibly carcinogenic to humans) and IQ is classified as a category 2A compound (probably carcinogenic to humans) by the International Agency for Research on Cancer.(11) Therefore, although the concentrations of HCA in food are low, they constitute a potential hazard, and there is concern regarding the carcino...

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Section: Discussionmentioning

confidence: 91%

“…IQ in the diet for 52 weeks. ( 47 ) Significant increases in CYP1A1 expression in the 100 p.p.m. group provide an alternative mechanism that can compensate for decreased CYP1A2 activity.…”

Section: Discussionmentioning

confidence: 99%

Low‐dose carcinogenicity of 2‐amino‐3‐methylimidazo[4,5‐f ]quinoline in rats: Evidence for the existence of no‐effect levels and a mechanism involving p21^{Cip / WAF1}

Wei¹,

Wanibuchi²,

Nakae³

et al. 2010

Cancer Science

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“…administration for 52 weeks significantly enhanced GST activity as well as UGT conjugating activity in F344 rats. (37) As mentioned above, GST is known as one of the most inducible prototypical phase II enzymes in the presence of Nrf2. (23) In fact, our data demonstrated that induction of GST activities did not occur following IQ exposure to Nrf 2(-/-) mice in either sex.…”

Section: Discussionmentioning

confidence: 97%

Increased susceptibility to hepatocarcinogenicity of Nrf2‐deficient mice exposed to 2‐amino‐3‐methylimidazo[4,5‐f]quinoline

Kitamura¹,

Umemura²,

Kanki³

et al. 2006

Cancer Science

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To elucidate the roles of the transcription factor NF-E2-related factor (Nrf2) in hepatocarcinogenesis induced by 2-amino-3-methylimidazo[4,5-f ]quinoline (IQ), a mutagenic and carcinogenic heterocyclic amine, Nrf2-deficient mice were treated with 300 p.p.m. IQ in their diet for 1, 4 or 52 weeks. In the long-term experiment, the multiplicity and incidence of liver tumors in male and female IQtreated Nrf2 deficient (-/-) mice were significantly higher than those in their counterpart wild-type (+/+) mice exposed to IQ. In the short-term experiment, although IQ exposure to Nrf2(+/+) mice of both sexes did not modify UDP-glucuronosyltransferase values, glutathione S-transferase values were significantly increased due to IQ treatment, in contrast to no alteration in male and female Nrf2(-/-) mice. Levels of oxidative stress markers such as 8-hydroxydeoxyguanosine and thiobarbituric acid reactive substances in the livers of all treated mice were not changed by IQ treatment. IQ-specific DNA adduct levels were elevated only in female Nrf2(-/-) mice, although the increase was not significant. IQ treatment caused an increase in proliferating cell nuclear antigen labeling indices only in male Nrf2(-/-) mice. The present data clearly show that Nrf2(-/-) mice of both sexes are susceptible to IQ hepatocarcinogenicity, which might result from IQ accumulation due to failure of metabolizing enzyme induction. In addition, inconsistent results concerning IQ-specific adducts and proliferating cell nuclear antigen labeling indices in male and female Nrf2(-/ (1) and also in cigarette smoke condensate (2) . IQ is carcinogenic to the liver, colon, small intestine, Zymbal's gland, clitoral gland and skin in F344 rats, (3) to the liver, forestomach and lung in CDF 1 mice, (4) and to the liver in B6C3F 1 mice (5) in long-term experiments. Recently, we have found that rat lung is also a target of IQ carcinogenicity.-(6) Its carcinogenesis is considered to involve mainly IQ bioactivation, that is phase I hepatic CYP1A1/2-mediated N-hydroxylation followed by phase II (mainly N-acetyltransferase and sulfotransferase) esterification of N-hydroxylamines to reactive ester derivatives that bind to DNA covalently. (7,8) In addition, it was suggested recently that oxidative stress may also participate in HCA carcinogenesis, based on the findings that induction of preneoplastic or neoplastic lesions following HCA exposure was significantly inhibited when given simultaneously with antioxidants in rats, (9,10) and that superoxide anion radicals were generated during metabolism of HCA by NADPH/cytochrome P-450 reductase in vitro using a spin-trapping method.(11) We have demonstrated enhancement of IQ-induced colon tumor development due to cotreatment with NaNO 2 and the participation of oxidative stress such as oxidative DNA damage and lipid peroxidation in this phenomenon. However, IQ-induced liver tumors were only slightly increased by the addition of NaNO 2 , the relation to oxidative stress being equivocal.(12) Thus, IQ causes carcinogenesis in a b...

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“…In addition, IQ itself is able to affect the activity of P450s enzymes depending on the treatment regimen [40]. Low P450s enzyme activity would delay the metabolic conversion of IQ into a substrate for GST enzymes and this may be one factor in the low mRNA levels of gpx1 after treatment with IQ.…”

Section: Discussionmentioning

confidence: 99%

Dammar resin, a non-mutagen, inducts oxidative stress and metabolic enzymes in the liver of gpt delta transgenic mouse which is different from a mutagen, 2-amino-3-methylimidazo[4,5-f]quinoline

Xie

Wei

Kakehashi

et al. 2012

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Contrasting effects of acute and chronic dietary exposure to 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) on xenobiotic metabolising enzymes in the male Fischer 344 Rat: implications for chemoprevention studies

Cited by 9 publications

References 43 publications

Low‐dose carcinogenicity of 2‐amino‐3‐methylimidazo[4,5‐f ]quinoline in rats: Evidence for the existence of no‐effect levels and a mechanism involving p21^{Cip / WAF1}

Low‐dose carcinogenicity of 2‐amino‐3‐methylimidazo[4,5‐f ]quinoline in rats: Evidence for the existence of no‐effect levels and a mechanism involving p21^{Cip / WAF1}

Increased susceptibility to hepatocarcinogenicity of Nrf2‐deficient mice exposed to 2‐amino‐3‐methylimidazo[4,5‐f]quinoline

Dammar resin, a non-mutagen, inducts oxidative stress and metabolic enzymes in the liver of gpt delta transgenic mouse which is different from a mutagen, 2-amino-3-methylimidazo[4,5-f]quinoline

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Contrasting effects of acute and chronic dietary exposure to 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) on xenobiotic metabolising enzymes in the male Fischer 344 Rat: implications for chemoprevention studies

Cited by 9 publications

References 43 publications

Low‐dose carcinogenicity of 2‐amino‐3‐methylimidazo[4,5‐f ]quinoline in rats: Evidence for the existence of no‐effect levels and a mechanism involving p21Cip / WAF1

Low‐dose carcinogenicity of 2‐amino‐3‐methylimidazo[4,5‐f ]quinoline in rats: Evidence for the existence of no‐effect levels and a mechanism involving p21Cip / WAF1

Increased susceptibility to hepatocarcinogenicity of Nrf2‐deficient mice exposed to 2‐amino‐3‐methylimidazo[4,5‐f]quinoline

Dammar resin, a non-mutagen, inducts oxidative stress and metabolic enzymes in the liver of gpt delta transgenic mouse which is different from a mutagen, 2-amino-3-methylimidazo[4,5-f]quinoline

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Low‐dose carcinogenicity of 2‐amino‐3‐methylimidazo[4,5‐f ]quinoline in rats: Evidence for the existence of no‐effect levels and a mechanism involving p21^{Cip / WAF1}

Low‐dose carcinogenicity of 2‐amino‐3‐methylimidazo[4,5‐f ]quinoline in rats: Evidence for the existence of no‐effect levels and a mechanism involving p21^{Cip / WAF1}