Metabolic activation of mycotoxins by animals and humans: An overview

Shank, Ronald C.

doi:10.1080/15287397709529526

Cited by 20 publications

(7 citation statements)

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“…These include hemangiosarcoma of the liver in workers exposed to vinyl chloride (Creech and Johnson, 1974), adenocarcinoma of the vagina in girls whose mothers had been treated with diethylstilbestrol during pregnancy (Herbst et al, 1971), and primary hepatic parenchymal cell tumors in men receiving anabolic steroids (Johnson et al, 1972) and young women taking oral contraceptives (Baum et al, 1973). Although less firmly established, the data presented by Shank at this symposium strongly indicate that aflatoxins are also carcinogenic in humans (Shank, 1977). It may also perhaps be assumed that the nitrosamines are human carcinogens, although the evidence is less good than for aflatoxins.…”

Section: Introductionmentioning

confidence: 88%

Extrapolation of cellular and molecular level studies to the human situation

1977

Journal of Toxicology and Environmental Health

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This presentation deals with aspects of extrapolation in the areas of carcinogenesis and mutagenesis. Although many chemicals are known to induce cancer in experimental animals, relatively few are recognized with certainty as carcinogenic in humans. A large number of N-nitroso compounds are potent carcinogens in animals and are useful models for extrapolation, although they are not proved human carcinogens.Prediction of carcinogenic activity from chemical structure is possible in some cases but is not generally reliable. Most carcinogens require metabolic activation by microsomal mixed-function oxidases, and phenobarbitone, an inducer of these enzymes, produces tumors of mouse liver similar to those produced by some organochlorine pesticides. Epidemiological studies in humans indicate that prolonged phenobarbitone intake does not significantly increase the incidence of any human tumor except in the brain. Liver tumor induction in mice may be markedly influenced by relatively small environmental changes. Several screening tests for carcinogenesis depend on extrapolation from molecular studies, including various in vitro assays and detection of interaction with DNA.Attempts to identify adducts of activated carcinogens with human cellular macromolecues have been made by several groups. Studies of the repair of DNA lesions induced by carcinogens may influence thinking on possible defense mechanisms of the body against cancer induction.

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Section: Introductionmentioning

confidence: 88%

Extrapolation of cellular and molecular level studies to the human situation

1977

Journal of Toxicology and Environmental Health

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“…[22,23] One study estimates the population attributable risk of AFB1-mediated HCC as 17% in some parts of the world. [24] Mechanistically, AFB1 is activated by CYP40s into AFB1-8,9-epoxide, which reacts with DNA, forming 8,9-dihydro-8-(N 7 -guanyl)-9-hydroxyaflatoxin B1 (AFB1-N 7 -guanine) adducts; these adducts, if left unrepaired, induce G>T transversions during DNA replication.…”

Section: Afb1mentioning

confidence: 99%

Roles of p53 in extrinsic factor-induced liver carcinogenesis

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Iwakuma

2017

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How to cite this article: Link T, Iwakuma T. Roles of p53 in extrinsic factor-induced liver carcinogenesis. Hepatoma Res 2017;3:95-104.Liver cancer remains one of the most common human cancers with a high mortality rate. Therapies for hepatocellular carcinoma (HCC) remain ineffective, due to the heterogeneity of HCC with regard to both the etiology and mutation spectrum, as well as its chemotherapy resistant nature; thus surgical resection and liver transplantation remain the gold standard of patient care. The most common etiologies of HCC are extrinsic factors. Humans have multiple defense mechanisms against extrinsic factor-induced carcinogenesis, of which tumor suppressors play crucial roles in preventing normal cells from becoming cancerous. The tumor suppressor p53 is one of the most frequently mutated genes in liver cancer. p53 regulates expression of genes involved in cell cycle progression, cell death, and cellular metabolism to avert tumor development due to carcinogens. This review article mainly summarizes extrinsic factors that induce liver cancer and potentially have etiological association with p53, including aflatoxin B1, vinyl chloride, non-alcoholic fatty liver disease, iron overload, and infection of hepatitis viruses. ReviewThis is an open access article distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms. Dr. Iwakuma's primary research focuses on the field of cancer research, specifically on cancer progression and metastasis in bone and soft tissue sarcoma, head and neck squamous cell carcinoma, and liver cancer. Over 50% of human cancer has mutations in the tumor suppressor p53 which regulates cell cycle progression, cell death, senescence, chromosome integrity, DNA repair, and metastasis. Therefore, understanding of the pathway involved in the regulation of p53 is essential for discovering novel cancer therapies. With special focus on the tumor suppressor p53 pathway, Dr. Iwakuma dissects the mechanism of cancer progression using genetically engineered mice, as well as tumor transplantation models, and applies disease models to translational research, to ultimately cure cancer.

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“…DMBA induces tumors predominantly in breast, skin, and lung; AFBl is a typical hepatocarcinogen [Newberne and Butler, 1969;Shank et al, 1972;DiGiovanni and Juchau, 19801. For both compounds, mutagenic effects are dependent on their metabolic transformation [Swenson et al, 1974;Shank, 1977;DiGiovanni and Juchau, 19801. (DMBA) and aflatoxin B1 (AFB1) were purchased from Sigma (Muenchen).…”

Section: Introductionmentioning

confidence: 99%

Comparison of S9 mix and hepatocytes as external metabolizing systems in Mammalian cell cultures: Cytogenetic effects of 7,12‐dimethylbenzanthracene and aflatoxin B1

et al. 1986

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Two external metabolizing systems, S9 mix from Aroclor-induced rat livers and freshly isolated hepatocytes, were used for activation in cultures of human lymphocytes and V79 cells. 7, 12-dimethylbenzanthracene (DMBA) and aflatoxin B1 (AFB1) were employed as indirectly acting reference mutagens. Mutagenic effects were measured by induction of sister chromatid exchange (SCE). With DMBA, SCE-inducing effects were found to be quite similar after activation by S9 mix and activation by hepatocytes. In human lymphocytes nearly the same dose-effect relationships were found with both metabolizing systems; in V79 cells the hepatocyte-mediated induction of SCE was detectable at slightly lower concentrations than the S9-mediated SCE induction. In contrast with AFB1, S9 activation led to a stronger SCE induction than hepatocyte activation in both target cells. The induction of chromosomal aberrations by AFB1 after activation by the two metabolizing systems was also analysed in V79 cells. This experiment again revealed that AFB1 was more efficiently activated by S9 mix than by hepatocytes, and it appeared that AFB1 is a more potent inducer of chromosomal aberrations than of SCE. The different activation capacities of the two metabolizing systems for AFB1 may be due to the maintenance of inactivation mechanisms in hepatocytes or to the Aroclor induction of the S9 fraction. Our experiments have shown that the suitability of hepatocytes as an activation system is not restricted to microbial or eukaryotic point mutation assays, but that hepatocyte metabolism can also be successfully included in cytogenetic tests with short- and long-term cultures of mammalian target cells.

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Metabolic activation of mycotoxins by animals and humans: An overview

Cited by 20 publications

References 49 publications

Extrapolation of cellular and molecular level studies to the human situation

Extrapolation of cellular and molecular level studies to the human situation

Roles of p53 in extrinsic factor-induced liver carcinogenesis

Comparison of S9 mix and hepatocytes as external metabolizing systems in Mammalian cell cultures: Cytogenetic effects of 7,12‐dimethylbenzanthracene and aflatoxin B1

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