Enhancing effects of phenobarbitone and butylated hydroxytoluene on 2-acetylaminofluorene-induced hepatic tumorigenesis in the rat

Peraino, Carl; Fry, R.J.M.; Staffeldt, E.; Christopher, John P.

doi:10.1016/s0015-6264(77)80311-8

Cited by 164 publications

(76 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This conclusion is supported by the work of Peraino et al (1971), Weisburger et al (1975) and McLean and Marshall (1971) and would support the view of Peraino et al (1975) that phenobarbitone-Na is not intrinsically tumorigenic and should be classified as an enhancer.…”

Section: Discussionsupporting

confidence: 56%

“…In the course of these experiments there have been no reports of hepatic carcinoma being directly attributable to the phenobarbitone (McLean and Marshall, 1971;Peraino et al, 1971;Weisburger et al, 1975). However, Peraino et al (1975) reported a single example of nodular hyperplasia in a study lasting 450 days, and Rossi et al (1977) a 59% incidence of liver-cell tumours. In the present study, no evidence of focal parenchymal cell hyperplasia was found before 80 weeks and, in the 33 animals examined between that time and the termination of the experiment at 104 weeks, 11 animals had evidence of focal nodular hyperplasia.…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Long-term effects of phenobarbitone-Na on male Fischer rats

Butler¹

1978

Br J Cancer

View full text Add to dashboard Cite

Summary.-Male inbred Fischer rats were fed phenobarbitone-Na at a level of 500 parts/106 in the diet for 1 week, followed by 1000 parts 106 for 103 weeks at which time the survivors were killed. Thirty-three treated rats survived to 80 weeks. Before 80 weeks, no animals showed hyperplastic lesions. Of the 33 rats surviving 80 weeks and more, 11 had foci of nodular hyperplasia. These foci were usually small, but one animal killed at 102 weeks had a lesion of 0 75 cm diameter, which compressed the surrounding liver. In no case was evidence of local invasion or metastasis found.All the livers had evidence of parenchymal cell damage. No evidence of nodular hyperplasia was found in the controls.It is concluded that there is no evidence to suggest that phenobarbitone-Na induced neoplasm in the liver of male Fischer rats.PHENOBARBITONE is a drug which is widely used therapeutically in long-term treatment. It is also used extensively in the study of the mechanism of enzyme induction, and has been shown to modify the effects of known hepatic carcinogens in the rat (Peraino et al., 1971). The longterm administration to mice of 2 strains demonstrated an increased incidence of hepatic nodules (Jones and Butler, 1975; Thorpe and Walker, 1973;Peraino et al., 1973). In the rat there is less information on long-term toxicity and while no full carcinogenicity study has been reported, Rossi et al. (1977) report the induction of hepatic nodules, designated as hepatomas.In this preliminary report, male rats of a strain known to be very sensitive to carcinogens have been fed phenobarbitone for 2 years. METHODMale inbred Fischer rats from a colony maintained in the Toxicology Unit, Medical Research Council Laboratories, Carshalton were used. Within a week of weaning, from a group of 75 selected at random, 50 rats were placed on a diet containing 500 parts/106 phenobarbitone-Na in MRC diet 41B. At the end of the first week, the concentration of the phenobarbitone-Na was increased to 1000 parts/106 in MRC diet 41B, and maintained at this level for the duration of the experiment. The remaining 25 male rats were maintained as controls on diet MRC 41B for 2 years. Water was available ad libitum.Initially the animals were weighed weekly, during the phase of rapid growth. Subsequently, they were weighed at 2-week intervals. Food consumption was measured weekly.Rats were killed when in poor condition and a complete necropsy examination was made. Of the animals found dead, 3 were too autolysed for useful histological study. Tissues from 47 treated and 25 control rats were examined. These tissues were fixed in formol saline, and processed into paraffin in the usual way. Sections were stained with Harris's haemotoxylin and eosin, and selected sections were stained by the periodic-acid-Schiff (PAS) reaction for glycogen and the van Giesson and Gordon Sweet methods for collagen and reticulin.

show abstract

Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 98%

Long-term effects of phenobarbitone-Na on male Fischer rats

Butler¹

1978

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…(2) a subsequent stimulation of growth of altered foci leading to malignant hepatocellular carcinoma (Pitot, 1977;Farber et al, 1977 (Takayama & Imaizumi, 1969;Scherer & Emmelot, 1975;Weisburger et al, 1975;Peraino et al, 1975;Solt & Farber, 1976;Pitot, 1977;Farber et al, 1977). It has been recently suggested that this second role may consist in creating a "cellular environment" favourable to the growth of preneoplastic lesions .…”

Section: Resultsmentioning

confidence: 99%

Effects of discontinuation of chronic feeding of diethylnitrosamine on the development of hepatomas in adult rats

Barbason¹,

Smoliar²,

Fridman-Manduzio³

et al. 1979

Br J Cancer

View full text Add to dashboard Cite

Summary.-Diethylnitrosamine (DENA) at 10 mg/kg/day was fed to adult rats either continuously or for periods ranging from 1 to 10 weeks. Survival correlated inversely with the duration of carcinogen feeding. Less than 4 weeks of DENA feeding produced only preneoplastic foci that persisted indefinitely; 4 weeks were found to be necessary for the transformation of preneoplastic lesions into liver cancers; after 6 weeks, the incidence of hepatomas was 100%. The process of liver cancerization appeared to be identical whether DENA was fed for 8 weeks or continuously up to the time of death. These results are discussed in the light of the evolution of the homoeostatic control of liver-cell division during DENA feeding, in order to distinguish the different successive roles played by the carcinogen.

show abstract

“…In humans and rodents, hepatocarcinogenesis is a multistep process (9,15,41,42,55). Basophilic foci are putative precursors of DEN-initiated mouse liver tumors (55), but only a small fraction of basophilic hepatic foci appear to progress to liver tumors.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Relationship Between Transforming Growth Factor-Alpha and Hepatic Focal Phenotype and Progression in Female Mouse Liver

1997

View full text Add to dashboard Cite

Modulations in the positive hepatocyte growth factor, transforming growth factor-alpha (TGF-α) and its receptor epidermal growth factor receptor (EGFR), occur in rat and human liver tumors. The purpose of this study was to determine if TGF-α and EGFR are altered in basophilic and acidophilic preneoplastic and neoplastic liver lesions generated in DEN-initiated mice exposed to a variety of hepatocarcinogens. Female B6C3F1 mice were initiated with N -nitrosodiethylamine (DEN) and treated with hepatocarcinogenic concentrations of unleaded gasoline vapor (2,000 ppm), methyl tertiary butyl ether vapor (7,814 ppm), phenobarbital (500 ppm, diet), or chlordane (25 ppm, diet). Hepatic foci and tumors were identified and evaluated immunohistochemically with antibodies for TGFα and EGFR. In all treatment groups, basophilic hepatic foci were negative for TGF-α immunoreactivity (554/564, 98%). In contrast, regardless of treatment, acidophilic hepatic foci were immunoreactive for TGF-α (107/108, 99%). There was no significant difference in mean hepatic labeling index as measured by the incorporation of 5-bromo-2'-deoxyuridine between foci immunoreactive and nonimmunoreactive for TGF-α. The incidence of immunoreactivity for TGF-α increased in hepatocellular tumors that were predominantly of the basophilic phenotype. Of basophilic hepatocellular adenomas, 16/81 (20%) were immunoreactive for TGF-α, while 17/29 (59%) of hepatocellular carcinomas stained positive for TGF-α. A similar increased incidence of EGFR immunoreactivity was found in basophilic hepatocellular adenomas (17/67, 25%) and carcinomas (19/28, 68%) relative to basophilic foci (11/367, 3%), suggesting an autocrine mechanism for the development of mouse liver tumors. The increased incidence of TGF-α immunoreactivity in basophilic liver tumors suggests that TGF-α is a marker of tumor progression in mouse liver. Furthermore, TGF-α modulations were dependent on phenotype rather than treatment, indicating inherent differences in the expression of TGF-α in basophilic and acidophilic hepatic lesions.

show abstract

Enhancing effects of phenobarbitone and butylated hydroxytoluene on 2-acetylaminofluorene-induced hepatic tumorigenesis in the rat

Cited by 164 publications

References 7 publications

Long-term effects of phenobarbitone-Na on male Fischer rats

Long-term effects of phenobarbitone-Na on male Fischer rats

Effects of discontinuation of chronic feeding of diethylnitrosamine on the development of hepatomas in adult rats

Quantitative Relationship Between Transforming Growth Factor-Alpha and Hepatic Focal Phenotype and Progression in Female Mouse Liver

Contact Info

Product

Resources

About