Detoxification of Genotoxic Compounds as a Threshold Mechanism Limiting Their Carcinogenicity

Flora, Silvio De

doi:10.1177/019262338401200406

Cited by 30 publications

(10 citation statements)

References 23 publications

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“…Several threshold mechanisms for genotoxic carcinogens have been suggested, including induction of detoxification processes, cell cycle delay, DNA repair, apoptosis and the suppression of neoplastically transformed cells by the immune system. ( 12,13,15,33 ) However, little in vivo evidence is available. To explore mechanisms underlying the carcinogenicity of low doses of IQ, we examined the relative mRNA expression of a panel of genes involved in cell proliferation, cell cycle regulation, DNA repair and IQ metabolic activation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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: 99%

“…This approach, however, is being challenged as advancements in the understanding of the molecular mechanisms of carcinogenesis are being made and experimental evidence showing that genotoxic carcinogens do not exert mutagenic and carcinogenic effects at low doses accumulates. ( 12–19 )…”

mentioning

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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“…NAC has also been shown to give local protection of the urinary tract against iphosphamide and cyclophosphamide induced toxicity (Holoye et al, 1983). In vitro, NAC is able to inhibit mutagens such as aflatoxin, benzpyrene and cigarette smoke condensate (de Flora, 1984;de Flora et al, 1984de Flora et al, , 1989. It prevents chemically induced lung and colon tumours in experimental animals.…”

Section: Head and Neck And Lung Cancermentioning

confidence: 99%

The EUROSCAN Study

Vries¹,

Zandwijk²,

Pastorino³

1991

Br J Cancer

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“…In fact, mutagens showing a trend to metabolic deactivation are often noncarcinogenic, contrary to theoretical expectations [4], This implies that these compounds can initiate cancer only in amounts saturating detoxification mech anisms. In other words, at least for some carcinogens, metabolic factors can be re sponsible for the occurrence of so-called thresholds [5,6] and therefore the aim of chemoprevention would be to raise such metabolic thresholds. In this context, it is well known that glutathione (GSH) plays a crucial role in the detoxification of xenobiotics, so that the term 'GSH threshold' has been coined [7], which applies to a large number of toxic, mutagenic and car cinogenic compounds.…”

Section: Role Of Metabolic Factors As Protective Mechanisms Against Mmentioning

confidence: 99%

Metabolic, Desmutagenic and Anticarcinogenic Effects of N-Acetylcysteine

Flora¹,

Rossi

Flora

1986

Respiration

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N-acetylcysteine (NAC) is often administered to respiratory patients with histories of exposure to noxious agents (e.g. cigarette smoke and atmospheric pollutants), which are known to act as glutathione (GSH) depletors and as cancer initiators and/or promoters. Since NAC is a precursor of intracellular GSH, we investigated its effects on GSH metabolism and on the biotransformation of carcinogenic and/or mutagenic compounds. In vitro, NAC induced a significant increase in oxidized glutathione (GSSG) reductase activity in rat liver preparations and counteracted the mutagenicity of direct-acting compounds (such as epichlorohydrin, hydrogen peroxide, 4-nitroquinoline-N-oxide and dichromate), as a result of its reducing and scavenging properties. At high concentrations, the drug completely inhibited the mutagenicity of procarcinogens (cigarette smoke condensate, tryptophan pyrolysate, cyclophosphamide, 2-aminofluorene, benzo(a)pyrene and aflatoxin B1) by binding their electrophilic metabolites. In contrast, their metabolic activation was stimulated by decreasing NAC concentrations, especially when liver preparations from enzyme-induced rats were used. Lung and liver subcellular preparations of rats treated in vivo with NAC, in various combinations with enzyme inducers and/or GSH depletors, also affected the mutagenicity of a number of compounds. NAC generally increased intracellular GSH and restored its levels following depletion. It did not affect the levels nor the spectral properties of cytochromes P-450 in pulmonary and hepatic microsomes, whereas it stimulated, especially in Aroclor-pretreated animals, cytosolic enzyme activities involved in NADP or GSSG reduction (G6PD, 6PGD and GSSG reductase) and in the reductive detoxification of xenobiotics (DT diaphorase). When administered with the diet, at a nontoxic posology (120 mg/kg b.w.), NAC markedly inhibited the induction of lung tumors in mice by a potent carcinogen (urethane)

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Detoxification of Genotoxic Compounds as a Threshold Mechanism Limiting Their Carcinogenicity

Cited by 30 publications

References 23 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}

The EUROSCAN Study

Metabolic, Desmutagenic and Anticarcinogenic Effects of N-Acetylcysteine

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Detoxification of Genotoxic Compounds as a Threshold Mechanism Limiting Their Carcinogenicity

Cited by 30 publications

References 23 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

The EUROSCAN Study

Metabolic, Desmutagenic and Anticarcinogenic Effects of N-Acetylcysteine

Contact Info

Product

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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}