Amitrole-induced cell transformation and gene mutations in Syrian hamster embryo cells in culture

Tsutsui, Takeki; Maizumi, Heiji; Barrett, J. Carl

doi:10.1016/0165-7992(84)90078-2

Cited by 22 publications

(5 citation statements)

References 8 publications

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“…Thus, it has been suggested that amitrole is a nonmutagenic carcinogen. Over the dose range that induced morphological transformation of Syrian hamster embryo cells in culture, amitrole induced gene mutations at the Na7/K+ ATPase and hypoxanthine phosphoribosyl transferase loci measured conc,omitantly in the same cells (91). These findings indicate that amitrole may act via a mutational mechanism and contrast with the negative results observed with bacterial and other mutation assays.…”

Section: Mutagenic Noncarcinogenscontrasting

confidence: 55%

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Mechanisms of Multistep Carcinogenesis and Carcinogen Risk Assessment

Barrett¹

1993

Environmental Health Perspectives

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Many different types ofchemical exposures can increase the incidence of tumors in animals and humans, but usually a long period of time is required before the carcinogenic risk of an exposure is manisfested. Both of these observations can be explained by a multistep/multigene model of carcinogenesis. In this model, a normal cell evolves into a cancer cell as the result of heritable changes in multiple, independent genes. The two-stage model of initiation and promotion for chemical carcinogenesis has provided a paradigm by which chemicals can act by qualitatively different mechanisms, but the process ofcarcinogenesis is now recognized as more complex than simply initiation and protion. Even a three-stage model of initiation, promotion, and progression, which can be operationally defined, is not adequate to describe the carcinogenic process. The number of genes altered in a cancer cell compared to a normal cell is not known; recent evidence suggests that3-10 genetic events are involvedin common adult magancesin humans. Carcinogenesis Is a Multistep ProcessCancer remains a major chronic health problem associated with toxicological substances. The long latency period of cancer induction (years in rodents and decades in humans) is a major problem in the evaluation of toxicological hazards and risk assessment. We understand, at least in part, the underlying reasons for the time requirement of cancer formation. It is now clear that for a normal cell to evolve into a cancer cell, multiple heritable changes within the cell are required, i.e., carcinogenesis is a multistep process involving multiple genes. Several lines of evidence support the conclusion that chemical carcinogenesis is a multistep process. These are listed in Table 1 and discussed in detail elsewhere (1).One of the underlying premises of most multistep models of carcinogenesis is that genetic and/or epigenetic alterations of multiple, independent genes are involved. Although the process of chemical carcinogenesis is often separated operationally into three stages, i.e., initiation, promotion, and progression (2), the number of genetic changes involved in each of these operationally defined stages has not yet been determined.Initiation involves the induction ofan irreversibly altered cell and is frequently equated with a mutational event. aSee Barrett (12) for a more complete discussion and references.

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Section: Mutagenic Noncarcinogenscontrasting

confidence: 55%

“…Amitrole, a widely used herbicide, is an animal carcinogen and an inducer of cell transformation (90,91). However, it is inactive as a mutagen in bacterial test systems (90).…”

Section: Mutagenic Noncarcinogensmentioning

confidence: 99%

Mechanisms of Multistep Carcinogenesis and Carcinogen Risk Assessment

Barrett¹

1993

Environmental Health Perspectives

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“…Amitrole induces a low level of morphological transformation of SHE cells (Pienta et al, 1977;Tsutsui et al, 1984). A weak increase in the transformation frequency was also observed in the present work.…”

Section: Discussionsupporting

confidence: 88%

Role of catalase and oxidative stress in hepatic peroxisome proliferator‐induced morphological transformation of syrian hamster embryo cells

Mikalsen

Kaalhus

Reith

et al. 1990

Intl Journal of Cancer

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Several hepatic peroxisome proliferators (HHPs) such as di(2-ethylhexyl)phthalate (DEHP), mono(2-ethylhexyl)-phthalate, clofibrate and tiadenol, induce morphological transformation of Syrian hamster embryo (SHE) cells in vitro. According to one hypothesis, the hepatocarcinogenic effect of HPPs is caused by an oxidative stress due to increased H2O2-production from the strongly induced peroxisomal beta-oxidation of fatty acids. Thus, increased transformation frequencies by HPPs should be obtained when catalase was inhibited by 3-amino-1,2,4-triazole (amitrole). However, co-exposure to HPPs and amitrole did not enhance the transformation frequencies for any of the HPPs. The sensitivity of SHE cells for oxidative agents was studied by using menadione and H2O2. Menadione only induced transformation at a toxic concentration, while H2O2 induced transformation at non-toxic concentrations. To study the generation of oxidative radicals in SHE cells, electron spin resonance was employed. No oxidative radical formation was detected in tiadenol- or DEHP-exposed SHE cells. When menadione or H2O2 were added during the measurements, oxidative radicals were found. A transmission electron microscopic study showed a small number of peroxisomes, and did not reveal any increase in the number of peroxisomes in clofibrate-treated SHE cells.

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“…The cytotoxic eŠects of arsenicals were determined by the MTT assay. 33,34) 例えば，amitrol, 35) asbestos, 33) di(2-ethylhexyl ) phthalate, 36) diethylstilbestrol, 37…”

Section: Fig 2 Cytotoxic Ešects Of Arsenic Compounds On Culturedmentioning

confidence: 99%

Induction of Aneuploidy, Centrosome Abnormality, Multipolar Spindle, and Multipolar Division in Cultured Mammalian Cells Exposed to an Arsenic Metabolite, Dimethylarsinate

Ochi

2016

YAKUGAKU ZASSHI

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Toxicological studies of arsenic compounds were conducted in cultured mammalian cells to investigate the effects of glutathione (GSH) depletion. Dimethylarsinate DMA(V) was not cytotoxic in cells depleted of GSH, but was found to be cytotoxic when GSH was present outside the cells. The results suggested that a reactive form of DMA(V) was generated through interaction with GSH. Dimethylarsine iodide DMI(III) was used as a model compound of DMA(III), and the biological effects were investigated. DMI(III) was about 10000 times more toxic to the cells than DMA(V). Chromosome structural aberrations and numerical changes, such as aneuploidy, were induced by DMI(III). DMA(V) induced multiple foci of the centrosome protein, γ-tubulin, which were colocalized with multipolar spindles in mitotic cells. The multiple foci coalesced into a single dot on disruption of the microtubules (MT). However, reorganization of the MT caused multiple foci of γ-tubulin, suggesting that the induction of centrosome abnormalities by DMA(V) required intact MT. Inhibition of the MT-dependent motor, kinesin, prevented formation of multiple foci of γ-tubulin, which pointed to the involvement of the MT-dependent mitotic motor, kinesin, in the maintenance of centrosome abnormalities. DMI(III) caused abnormal cytokinesis (multipolar division). In addition, DMI(III) caused morphological transformation in Syrian hamster embryo cells. Consideration of the overall process following the centrosome abnormalities caused by DMA(V) suggested a mode of cytotoxicity in which the mitotic centrosome is a critical target.

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Amitrole-induced cell transformation and gene mutations in Syrian hamster embryo cells in culture

Cited by 22 publications

References 8 publications

Mechanisms of Multistep Carcinogenesis and Carcinogen Risk Assessment

Mechanisms of Multistep Carcinogenesis and Carcinogen Risk Assessment

Role of catalase and oxidative stress in hepatic peroxisome proliferator‐induced morphological transformation of syrian hamster embryo cells

Induction of Aneuploidy, Centrosome Abnormality, Multipolar Spindle, and Multipolar Division in Cultured Mammalian Cells Exposed to an Arsenic Metabolite, Dimethylarsinate

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