Absence of DNA Adduct Formation by Phenobarbital, Polychlorinated Biphenyls, and Chlordane in Mouse Liver Using the32P-Postlabeling Assay

Whysner, John; Montandon, F.; McClain, R.M.; Downing, John C.; Verna, Lynne; Steward, Robert E.; Williams, Gary M.

doi:10.1006/taap.1997.8311

Cited by 47 publications

(16 citation statements)

References 35 publications

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“…However, in vivo, no evidence for DNA reactivity could be observed, which might be the result of the low metabolic rate of these compounds using either higher-chlorinated [Nath et al, 1991;Whysner et al, 1998] or lower-chlorinated (this study) PCB mixtures. We therefore conclude that, although PCBs are capable of inducing genotoxic damage in unprotected DNA, cellular defense mechanisms are apparently capable of preventing DNA adduct formation after a single exposure in intact organisms.…”

Section: Discussionmentioning

confidence: 84%

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Induction of DNA adducts by several polychlorinated biphenyls

Schilderman

Maas

Pachen

et al. 2000

Environ. Mol. Mutagen.

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Section: Discussionmentioning

confidence: 84%

“…Moreover, Aroclor 1260 was tested for DNA adduct formation in the liver of B6C3F1 mice after either single-or 2-week dietary exposure. Negative results were obtained for DNA of the liver of the different treatment groups [Whysner et al, 1998]. …”

Section: Discussionmentioning

confidence: 99%

Induction of DNA adducts by several polychlorinated biphenyls

Schilderman

Maas

Pachen

et al. 2000

Environ. Mol. Mutagen.

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“…In terms of a genotoxic MOA, PB has been shown to be negative in a wide range of genotoxicity tests and does not form adducts with DNA (IARC, 2001; Whysner et al, 1996, 1998). Liver tumors can be induced in rodents by cytotoxic agents such as chloroform (Meek et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator

Elcombe¹,

Peffer

Wolf

et al. 2013

Critical Reviews in Toxicology

226

219

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The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are important nuclear receptors involved in the regulation of cellular responses from exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non-genotoxic indirect CAR activator, which induces cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes and is known to produce liver foci/tumors in mice and rats. From literature data, a mode of action (MOA) for PB-induced rodent liver tumor formation was developed. A MOA for PXR activators was not established owing to a lack of suitable data. The key events in the PB-induced liver tumor MOA comprise activation of CAR followed by altered gene expression specific to CAR activation, increased cell proliferation, formation of altered hepatic foci and ultimately the development of liver tumors. Associative events in the MOA include altered epigenetic changes, induction of hepatic CYP2B enzymes, liver hypertrophy and decreased apoptosis; with inhibition of gap junctional intercellular communication being an associative event or modulating factor. The MOA was evaluated using the modified Bradford Hill criteria for causality and other possible MOAs were excluded. While PB produces liver tumors in rodents, important species differences were identified including a lack of cell proliferation in cultured human hepatocytes. The MOA for PB-induced rodent liver tumor formation was considered to be qualitatively not plausible for humans. This conclusion is supported by data from a number of epidemiological studies conducted in human populations chronically exposed to PB in which there is no clear evidence for increased liver tumor risk.

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“…Metabolic activation of labeled PCBs has been shown to result in protein, RNA and DNA binding of radioactivity (Seymour et al, 1976;Wyndham and Safe, 1978;Morales and Matthews, 1979). DNA adducts have been detected for PCBs incubated with mouse, rat and human hepatic microsomes (Schilderman et al, 2000;Pereg et al, 2002) or with fetal rat hepatocytes and HepG2 cells (Dubois et al, 1995), whereas negative results were obtained for DNA from the livers of both male and female mice receiving either single or 2-week dietary exposures (Whysner et al, 1998). Recently, Aroclor 1254, Aroclor 1016 and 4-chlorobiphenyl have been found to cause DNA adducts formation in primary cultures of human hepatocytes (Borlak et al, 2003).…”

Section: Polychlorinated Biphenylsmentioning

confidence: 92%