The effect of long-term administration of phenobarbitone in CF-1 mice

Ponomarkov, V.; Tomatis, Lorenzo; Turusov, V. S.

doi:10.1016/s0304-3835(75)96367-3

Cited by 43 publications

(10 citation statements)

References 13 publications

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“…In the initiation stage, the rats were given 0.02% 2-AAF in the diet for 4 weeks, or 0.01% BBN in the drinking water for 4 weeks, or neither 2-AAF nor BBN for 4 weeks. The results are consistent with the findings that phenobarbital did not enhance 7,12-dimethylbenz(a)anthracene-induced skin tumors (16) or dimethylnitrosamine-induced lung tumors and that phenobarbital increased the incidence of spontaneous liver tumors, but had no effect on the incidence of other spontaneous tumors (17). The experimental protocol is shown in Figure 5.…”

Section: Organ-specific Effects Of Promoterssupporting

confidence: 89%

Effects of Promoters on N-Butyl-N-(4-hydroxybutyl)nitrosamine-Induced Urinary Bladder Carcinogenesis in the Rat

Ito¹,

Fukushima²,

Shirai³

et al. 1983

Environmental Health Perspectives

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JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org.. The National Institute of Environmental Health Sciences (NIEHS) and Brogan & Partners are collaborating with JSTOR to digitize, preserve and extend access to Environmental Health Perspectives.It has been shown that the occurrence of the preneoplastic lesion, papillary or nodular hyperplasia (PN hyperplasia) in rat urinary bladder induced by carcinogens is correlated with that of cancer. Therefore, the promoting effects of chemicals in two-stage bladder carcinogenesis were judged by measuring their ability to induce PN hyperplasia in rats. Male rats were given N-butyl-N44-hydroxybutyl)nitrosamine (BBN) for 4 weeks and then one of 16 test chemicals for 32 to 34 weeks. Saccharin, ascorbate, DL-tryptophan, allopurinol, and diphenyl promoted development of PN hyperplasia. The dose-response of the promoters were examined in both sexes of rats by administration of saccharin at doses of 0.04, 0.2, 1.0 and 5.0% for 32 weeks after BBN treatment. The occurrence of PN hyperplasia was significantly increased in the group given 5% saccharin. Dose-response curves showed enhanced hyperplastic responses in both sexes given 0.2 to 5% saccharin.The organ specificities of promoters were studied in rats initiated with BBN or 2-acetylaminofluorene (2-AAF) followed by phenobarbital or saccharin for 32 weeks. Phenobarbital greatly enhanced hepatocarcinogenesis. Saccharin significantly enhanced the occurrence of both BBN-induced and 2-AAF-induced PN hyperplasia. However, there was no effect of phenobarbital on the urinary bladder or of saccharin on the liver.The rats showed a strain difference in susceptibility of the urinary bladder to saccharin; ACI rats were most susceptible and Sprague Dawley rats were most resistant to saccharin.The membrane potential of superficial epithelial cells in the urinary bladder of rats treated with saccharin was measured with an intracellular microelectrode and found to be higher than that of controls.

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Section: Organ-specific Effects Of Promoterssupporting

confidence: 89%

Effects of Promoters on N-Butyl-N-(4-hydroxybutyl)nitrosamine-Induced Urinary Bladder Carcinogenesis in the Rat

Ito¹,

Fukushima²,

Shirai³

et al. 1983

Environmental Health Perspectives

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“…Unfortunately, in many of these studies PB or NaPB was administered only at a single dose level, hence dose–response relationships for liver tumor formation were not evaluated. For example, PB or NaPB produced liver tumors in C3H and CF-1 strain mice when administered either at 500 ppm (0.05%) in the drinking water or at 500 ppm in the diet, giving daily intakes of ~65–70 mg/kg day (Peraino et al, 1973; Ponomarkov et al, 1976; Thorpe & Walker, 1973). Although marked mouse strain differences in susceptibility to spontaneous liver tumor formation are known to exist (Becker, 1982), PB has been shown to produce liver tumors in both high (C3H/He) and low (C57BL/6) spontaneous incidence strains when administered in the diet to provide a daily intake level of 85 mg/kg day (Evans et al, 1986, 1992).…”

Section: Introductionmentioning

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

228

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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“…Furthermore, although styrene administration does not cause tumors in rats (9), lung tumors have been observed in mice by Ponomarkov and Tomatis (19) and Cruzan et al (8). Cruzan et al (10) examined the effect of inhaled styrene on the lungs of mice.…”

Section: Introductionmentioning

confidence: 99%

4-Vinylphenol-Induced Pneumotoxicity and Hepatotoxicity in Mice

et al. 2002

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4-Vinylphenol (4-hydroxystyrene , 4-ethenylphenol , 4-VP) occurs naturally in some foods and has been used as a avoring agent in food products. It is used synthetically in the production of polymers and resins. It has also been reported to be a minor metabolite of styrene in rats and humans. Varying doses of 4-vinylpheno l were administered ip to mice. Hepatotoxicity was assessed by measuring serum sorbitol dehydrogenas e (SDH) and by light microscopy. Pneumotoxicity was assessed by measuring proteins, cells, and lactate dehydrogenas e activity in bronchoalveola r lavage uid (BALF) and by light microscopy. 4-VP caused a dose-dependen t increase in serum SDH and mild hepatocellular swelling. It caused an increase in cell number and lactate dehydrogenas e activity in BALF. Microscopically, there was widespread and severe necrosis of the bronchioles by 12 hours. Re-epithelialzation of the bronchioles was evident by 48 hours. These studies indicate that 4-vinylphenol is both hepatotoxi c and pneumotoxic.

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The effect of long-term administration of phenobarbitone in CF-1 mice

Cited by 43 publications

References 13 publications

Effects of Promoters on N-Butyl-N-(4-hydroxybutyl)nitrosamine-Induced Urinary Bladder Carcinogenesis in the Rat

Effects of Promoters on N-Butyl-N-(4-hydroxybutyl)nitrosamine-Induced Urinary Bladder Carcinogenesis in the Rat

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

4-Vinylphenol-Induced Pneumotoxicity and Hepatotoxicity in Mice

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