The dual role of 2-acetylaminofluorene in hepatocarcinogenesis: Specific targets for initiation and promotion

Neumann, Hans‐Günter; Bitsch, Annette; Klöhn, Peter-Christian

doi:10.1016/s0027-5107(97)00040-7

Cited by 14 publications

(9 citation statements)

References 23 publications

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“…These findings again demonstrate that cytoxicity, which was not apparent in conventional histologic preparations, led to reparative cell proliferation, which increased disproportionately to exposure. Some mechanisms for hepatotoxicity of AAF have been described by Neumann et al (1997), albeit at higher exposures (-fourfold) than the highest used here.…”

Section: 26mentioning

confidence: 68%

“…The basis for such enhancement probably resides in the reduced opportunity for repair of DNA damage before the cell replicates its DNA, as also demonstrated by the enhancing effect of cell proliferation on the mutagenic effects of DNA-reactive chemicals in cultured liver cells (Berman et al, 1978;Tong et al, 1980). Other investigators have described a "promoting" effect of AAF in liver carcinogenesis at much higher doses than those used here (about 4-to 10-fold) (Saeter et al, 1988;Neumann et al, 1997), but have not reported on levels of cell proliferation, which could also contribute to neoplastic development (Williams, 1981(Williams, , 1992.…”

Section: 26mentioning

confidence: 71%

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Nonlinearities in 2-Acetylaminofluorene Exposure Responses for Genotoxic and Epigenetic Effects Leading to Initiation of Carcinogenesis in Rat Liver

Williams¹

1998

Toxicological Sciences

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R. (1998). Toxicol. Sci. 45,[152][153][154][155][156][157][158][159][160][161] The dose responses for several effects of low-level limited exposures to 2-acetylaminofluorene (AAF) in the livers of male Fischer 344 rats were measured and a subsequent phenobarbital tumor promotion regimen was used to manifest initiation of carcinogenesis. Three doses over a 10-fold range yielding cumulative total exposures of 0.126,0.42, and 1.26 mmol AAF/kg body weight were achieved by daily intragastric instillation for up to 12 weeks with interim terminations. This was followed by 24 weeks administration of 500 ppm phenobarbital (PB) in the diet to promote liver tumor development. At 12 weeks at the end of AAF administration, all exposures produced adducts in liver DNA, measured by 32 P postlabeling, and the level of adducts increased with exposure, except that the high exposure did not produce a dose proportional increase. Measurement of arylsutfotransferase activity, a key enzyme in the metabolic activation of AAF, revealed that in livers from the high exposure animals, the enzyme was inhibited. To assess for toxicity, the centrilobular zone of glutamine synthetasepositive hepatocytes was quantified immunohistochemically at 12 weeks. The area of the zone was reduced in the high exposure group and there was a trend to reduction in relationship to exposure. The two lower exposures to AAF produced no increase in cell proliferation, whereas the high exposure resulted in a marked increase, about 8-fold over controls. Initiation was assessed by induction of hepatocellular altered foci (HAF) that expressed the placental form of glutathione 5-transferase. AAF induced HAF in the high exposure group, 9-fold at 8 weeks and 170-fold at 12 weeks compared to controls. In rats maintained on PB for 24 weeks after exposure, the multiplicity of HAF increased in controls and comparably in the low and mid exposure groups, but remained at the about the same high level in the high exposure group. The high exposure produced a substantial incidence of benign neoplasms by 12 weeks, and with promotion by 36 weeks, all rats developed hepatocellular neoplasia. In the mid exposure

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Section: 26mentioning

confidence: 68%

Section: 26mentioning

confidence: 71%

Nonlinearities in 2-Acetylaminofluorene Exposure Responses for Genotoxic and Epigenetic Effects Leading to Initiation of Carcinogenesis in Rat Liver

Williams¹

1998

Toxicological Sciences

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“…Several PCNA immunoreactivity studies have been conducted on human livers exhibiting chronic liver diseases and hepatocellular carcinomas. 16,[35][36][37][38][39][40][41][42] Normal liver tissue exhibited minimal PCNA levels, whereas hepatocellular carcinomas (HCCs) exhibited increasing PCNA levels that corresponded with tumor grade. For example, 1 study indicated that the PCNA levels in HCC grades 1, 2, 3, and 4 were 12.2%, 17.5%, 53.7%, and 83.9%, respectively.…”

Section: Discussionmentioning

confidence: 99%

Cellular Proliferation, Cell Death, and Liver Histology in Gambusia affinis After Dietary Exposure to Benzidine and 2-Aminofluorene

et al. 2010

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Chronic exposure to arylamines through diet and/or smoking has been associated with genetic changes and tumorigenesis. Cellular proliferation, apoptosis, and histological changes in liver tissue were investigated in Gambusia affinis ( G affinis) after chronic dietary exposure to 6.9 mM and 0.069 mM concentrations of benzidine (BZ), 2-aminofluorene (2AF), and their combination for 4, 8, and 12 weeks, respectively. The proliferation assay indicated non–dose-dependent increases in cellular proliferation over the controls for all treatment groups at 4 and 12 weeks but not at 8 weeks except for the low dose of 2AF. The apoptosis assay showed effects in the low-dose group of 2AF and BZ at 4 weeks only. Hematoxylin/eosin staining of liver tissue revealed an increase in oval/spindle cell proliferation and altered foci formation in the treated groups compared with controls. These results demonstrate a mammalian-like response to 2AF and BZ in G affinis liver.

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“…Two of the active metabolites of AAF, i.e., N-hydroxy-AF and 2-nitrosofluorene (see Fig. 1) are highly effective in inducing a redox cycle at complex I and complex III of the mitochondrial respiratory chain, thereby impairing mitochondrial respiration and oxidative phosphorylation (Neumann et al 1997;Klöhn et al 1998Klöhn et al , 2003. Initially, this leads to an opening of the mitochondrial permeability transition pore (PTP) and depolarization of the mitochondrial membrane, followed by nuclear apoptosis and regenerative proliferation leading to cirrhosis-like transformation of liver tissue.…”

Section: Mechanistic Studies On Organotropism and Dose-response Relatmentioning

confidence: 99%

The life of Hans-Günter Neumann and his contributions to chemical carcinogenesis

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The dual role of 2-acetylaminofluorene in hepatocarcinogenesis: Specific targets for initiation and promotion

Cited by 14 publications

References 23 publications

Nonlinearities in 2-Acetylaminofluorene Exposure Responses for Genotoxic and Epigenetic Effects Leading to Initiation of Carcinogenesis in Rat Liver

Nonlinearities in 2-Acetylaminofluorene Exposure Responses for Genotoxic and Epigenetic Effects Leading to Initiation of Carcinogenesis in Rat Liver

Cellular Proliferation, Cell Death, and Liver Histology in Gambusia affinis After Dietary Exposure to Benzidine and 2-Aminofluorene

The life of Hans-Günter Neumann and his contributions to chemical carcinogenesis

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