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}

Abstract

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...

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

“…However, in the present study, IQ did not induce 8-OHdG formation. Our result was consistent with the studies of Kitamura et al [26] and Wei et al [22]: the level of 8-OHdG was not significantly changed in the livers of rats treated with 300 ppm IQ.…”

“…Primers and probes (Taqman Gene Expression Assay) were purchased from Applied Biosystems, Inc., Carlsbad, CA, USA. The PCR program cycles were set as follows: initial denaturing at 95 • C for 20 s, followed by 40 cycles at 95 • C for 3 s, and 60 • C for 30 s. PCR reactions were performed as described previously [22], with primers for mouse p53, bax, bcl-2, caspase-3, cyp1a1, cyp1a2, cyp2e1, cyp2r1, cyp7b1, gpx1 and gstm2. ␤-Actin mRNA was employed as an internal standard, and the mRNA levels of the target gene were normalized to the ␤-actin mRNA level.…”

Lack of Hepatocarcinogenicity of Combinations of Low Doses of 2-amino-3, 8-dimethylimidazo[4,5-<i>f</i>]quinoxaline and Diethylnitrosamine in Rats: Indication for the Existence of a Threshold for Genotoxic Carcinogens

“…Anti-rat GST-P polyclonal antibody (Medical and Biological Laboratories Co., Ltd., Nagoya, Japan) at a dilution of 1:1000 was used for immunohistochemical staining of GST-P. GST-P-positive hepatocellular foci composed of 2 or more cells were counted under a light microscope 2 , 12 , 14 , 15 . Total areas of livers were measured using an IPAP color image processor (Sumica Technos, Osaka, Japan), and the number of GST-P-positive foci per square centimeter of liver tissue was calculated.…”

“…It is generally assumed that genotoxic carcinogens exert a non-threshold carcinogenic effect. This concept, however, is being challenged, as advancements in the understanding of the molecular mechanisms of carcinogenesis are being made and experimental evidence continues to accumulate showing that individual genotoxic carcinogens do not exert mutagenic or carcinogenic effects at low doses 1 , 2 , 3 , 4 , 5 , 6 . Given the probability that humans are exposed concurrently or sequentially to trace concentrations of multiple environmental carcinogens, examination of the effects of combinations of low doses of genotoxic carcinogens is an indispensable part of cancer risk assessment.…”

Study of Electrochemical Water Reactor Concerning Food Safety in Industerial Food Processing

“…The effect of activated water on complex compositions such as viruses, bacteria and unnatural cells can be explained by physical entity, fundamentality, and electromagneticity such as complex interactions and destructive alternating structure collision (5,6).…”