A comparative study of the efficacy of four barbiturates as promoters of the development of γ-glutamyltranspeptidase-positive foci in the liver of carcinogen treated rats

Shinozuka, Hisashi; Lombardi, Benito; Abanobi, Samuel E.

doi:10.1093/carcin/3.9.1017

Cited by 36 publications

(8 citation statements)

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“…In particular, strong liver enzyme inducers like phenobarbital, which causes CYP 2B 1/2 elevation, are well known to be hepatic tumor promoters (16). In contrast, the related amobarbital, pentobarbital, and barbituric acid are only weak inducers of CYP 2B 1/2 enzymatic activity and are relatively ineffective promoters of rat hepatocarcinogenesis (4,19,21 In the present study, the numbers of GST-P-positive single cells and mini foci were significantly increased in the DEN-initiated groups treated with ~1,800 ppm. Since it has been established that nongenotoxic chemicals that cause increases in the number of GST-P-positive foci in 2-stage hepatocarcinogenesis models are likely to be liver tumor promoters (9), this might explain the tendency for increased hepatic tumors in the carcinogenicity study of fenbendazole (23).…”

Section: Fenbendazole [Methyl 5-(phenylthio)-2-benzimidazolecontrasting

confidence: 50%

Liver Tumor Promoting Effects of Fenbendazole in Rats

Shoda

Oda

Takeda³

et al. 1999

Toxicol Pathol

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In order to examine whether fenbendazole has tumor-promoting activity, a total of 70 male Fischer 344 rats were initiated with a single intraperitoneal injection of 100 mg/kg of diethylnitrosamine (DEN) or were given the saline vehicle alone; beginning 1 wk later, rats were given a diet containing 3,600; 1,800; 600; 200; 70; or 0 ppm of fenbendazole for 8 wk. Subgroups of 5 rats each from the DEN+1,800; DEN+0; 1,800; and 0 ppm groups were euthanatized after 1 wk of fenbendazole treatment, and the remaining animals were euthanatized at 8 wk. After 1 wk, relative liver weights (ratios to body weights) were significantly increased in the DEN+1,800 and 1,800 ppm groups, and based on light microscopy, periportal hepatocellular hypertrophy was evident in these groups. After 8 wk, relative liver weights were significantly increased in the groups given ≥600 ppm with or without DEN initiation. Periportal hepatocellular hypertrophy, characterized by a marked increase in smooth endoplasmic reticulum, was observed in the groups given ≥600 ppm with or without DEN initiation. Induction of cytochrome P-450 (CYP) 1A2, 2B1, or 4A1 was noted in the fenbendazoletreated groups with or without DEN initiation; that associated with CYP 1A2 was most marked. Positive immunostaining for anti-CYP 1A1/2 or CYP 2B1/2 was observed diffusely in the livers of animals in the DEN+1,800 and DEN+3,600 ppm groups. The numbers and areas of connexin 32 (Cx32)-positive spots per square centimeter in centrilobular hepatocytes were significantly decreased in an almost dose-dependent manner with fenbendazole treatment after DEN initiation. In situ hybridization for Cx32 mRNA revealed a remarkable decrease in its expression in the centrilobular hepatocytes in the DEN+70 ppm group. The numbers of glutathione Stransferase placental-form positive single cells (plus mini foci) were significantly increased in the DEN+1,800 and DEN+3,600 ppm groups. Since those agents that induce CYP 2B1/2 isozymes and reduce Cx32 in centrilobular hepatocytes have been suggested to be liver tumor promoters, the present results indicate that fenbendazole may be a liver tumor promoter.

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Section: Fenbendazole [Methyl 5-(phenylthio)-2-benzimidazolecontrasting

confidence: 50%

Liver Tumor Promoting Effects of Fenbendazole in Rats

Shoda

Oda

Takeda³

et al. 1999

Toxicol Pathol

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“…A number of compounds have been identified as promoters in experimental hepatocarcinogenesis. These include the barbiturates, PB and barbital, cyclic chlorinated compounds, DDT, a and g-hexachlorocyclohexane, mixed polychlorinated biphenyls, anti-oxidant butylated hydroxytoluene, hypolipidaemic drug nafenopin, estrogen mestranol, steroids, and dexamethasone [23][24][25][26][27]. Even though all these agents act as liver tumor promoters, the mechanisms by which they influence tumor promotion are different.…”

Section: Discussionmentioning

confidence: 99%

Tumor promotion by metanil yellow and malachite green during rat hepatocarcinogenesis is associated with dysregulated expression of cell cycle regulatory proteins

Gupta

Sundarrajan

Rao

2003

Teratog. Carcinog. Mutagen.

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Metanil yellow (MY) and malachite green (MG) are textile dyes, which, despite a ban, are used as food-coloring agents. MY and MG have promoter effects on the development of hepatic preneoplastic lesions induced by N-nitrosodiethylamine (DEN). Tumor-promoting agents are not mutagenic but may alter the expression of genes whose products are associated with hyper-proliferation, tissue remodeling, and inflammation. Cell cycle controls normally function to ensure the integrity of the genome and arrest of cells at G1/S or G2/M checkpoints until all the prerequisite events are completed. In order to understand the mechanism(s) of tumor promotion by MY and MG, we have studied the levels of PCNA, a marker of cell proliferation and cell cycle regulatory proteins, cyclin D1, and its associated kinase, cdk4, cyclin B1, and associated kinase, cdc2. Immunohistochemical staining showed an elevated level of PCNA in animals administered MY and MG subsequent to DEN treatment. Western and Northern blot hybridization showed an increased expression of both cyclin D1 and its associated kinase cdk4, and cyclin B1 and its associated kinase cdc2, in livers of rats administered MY and MG after administration of DEN as compared to untreated or DEN controls. The increased level of mRNA was due to the increased rate of transcription of these genes as studied by run-on transcription assay. These data obtained by the in vivo model of liver tumor development provide strong evidence From for a link between dysregulation of the two critical checkpoints of the cell cycle as one of the possible mechanism(s) during tumor promotion by malachite green and metanil yellow.

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“…In contrast to its strong effects, the related barbiturates amobarbital, pentobarbital, and barbituric acid cause weak CYP 2B 1/2 induction and are relatively weak promoters of rat liver tumor development (6,17,20). In a recent study, fenbendazole had liver tumor-promoting activity, strongly induced CYP lA2 and CYP 2B l, and 2-tailed test.…”

Section: Discussionmentioning

confidence: 99%

Live Tumor-Promoting Effect of β-Naphthoflavone, a Strong CYP 1A1/2 Inducer, and the Relationship between CYP 1A1/2 Induction and Cx32 Decrease in Its Hepatocarcinogenesis in the Rat

et al. 2000

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Interrelationships among induction of cytochrome P-450 (CYP) 1A1/2, decrease in connexin 32 (Cx32), and liver tumor-promoting activity by β-naphthoflavone (BNF) in the promotion stage were examined in a 2-stage liver carcinogenesis model. A total of 20 male Fischer 344 rats were initiated with a single intraperitoneal injection of 150 mg/kg of diethylnitrosamine (DEN) or were given the saline vehicle alone. Starting 2 weeks later, they were fed a diet containing 2%, 1%, or 0% BNF for 6 weeks. All animals were subjected to a two-thirds partial hepatectomy at week 3 and were sacrificed at week 8. Absolute and relative liver weights were significantly increased in the DEN+BNF groups as compared to the DEN-alone group. Diffuse hepatocellular hypertrophy with cytoplasmic eosinophilia, sometimes accompanied by development of adenoma-like hepatic foci, was observed in the BNF-treated rats. Remarkable induction of cytochrome CYP 1A1/2 and significant increase in CYP 2E1 were noted in the DEN+BNF groups, and positive immunohistochemical staining for both was observed diffusely. The areas of Cx32-positive spots per hepatocyte in the centrilobular areas of livers of the BNF-treated rats were significantly decreased, but no changes were observed in periportal areas. The numbers and areas of foci positive for glutathione S-transferase placental form were increased in the BNF-treated groups. These results suggest that BNF is a liver tumor promoter that, unlike phenobarbital, does not induce CYP 2B1/2 isozymes, and there seems to be no direct relationship between CYP 1A1/2 induction and Cx32 reduction in BNF hepatocarcinogenesis.

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A comparative study of the efficacy of four barbiturates as promoters of the development of γ-glutamyltranspeptidase-positive foci in the liver of carcinogen treated rats

Cited by 36 publications

References 0 publications

Liver Tumor Promoting Effects of Fenbendazole in Rats

Liver Tumor Promoting Effects of Fenbendazole in Rats

Tumor promotion by metanil yellow and malachite green during rat hepatocarcinogenesis is associated with dysregulated expression of cell cycle regulatory proteins

Live Tumor-Promoting Effect of β-Naphthoflavone, a Strong CYP 1A1/2 Inducer, and the Relationship between CYP 1A1/2 Induction and Cx32 Decrease in Its Hepatocarcinogenesis in the Rat

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