DNA reactive and epigenetic carcinogens

Williams, Gary M.

doi:10.1016/s0940-2993(11)80158-2

Cited by 48 publications

(25 citation statements)

References 20 publications

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“…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: 77%

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: 77%

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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“…Another mechanism that has been proposed for the hepatocarcinogenicity of PPAs is enhancement of cell proliferation (Marsman et uZ. 1988), which could be the basis for neoplastic transformation or development through a variety of mechanisms (Cohen and Ellwein 1990;Williams 1992). The role of cell proliferation, however, is uncertain inasmuch as some studies have not found an association with hepatocarcinogenesis (Rao and Reddy 1989;Eacho et al 1992).…”

Section: Cell Proliferationmentioning

confidence: 99%

“…Nevertheless, the possibility exists that exposures to humans may be below that required for enhancement of cell proliferation, but this requires documentation. Enhanced cell proliferation has been implicated in neoplastic transformation in rodent liver (Buttenvorth 1990;Williams 1992), but no evidence exists for human liver. Accordingly, it re- mains uncertain whether enhanced cell proliferation would occur in human liver and, even if it did, whether it would lead to neoplasm development.…”

Section: Cell Proliferationmentioning

confidence: 99%

Mechanism‐based Risk Assessment of Peroxisome Proliferating Rodent Hepatocarcinogens

Williams

Perrone

1996

Annals of the New York Academy of Sciences

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“…This aspect remains controversial 6 . The mode of action of some carcinogens entails epigenetic or nongenotoxic mechanisms which do not involve reactivity of the chemical with DNA, but rather other cellular effects 7 . This type of effect is produced only at exposures that elicit cellular responses, such as proliferation, which underlie the carcinogenic response.…”

Section: Introductionmentioning

confidence: 99%