Skip to main content
NCBI home page
British Journal of Experimental Pathology logoLink to British Journal of Experimental Pathology
. 1986 Feb;67(1):131–139.

Dose-response relationship for phenobarbitone promotion of liver tumours initiated by single dose dimethylnitrosamine.

H E Driver, A E McLean
PMCID: PMC2013072  PMID: 3947531

Abstract

A single dose of 15 mg/kg dimethylnitrosamine is an initiator of hepatic tumour formation in rats but does not produce tumours without further treatment. Subsequent promotion by Na phenobarbitone (1000 micrograms/ml drinking water) leads to 40% or more of the rats developing hepatocellular carcinoma. Four days of dietary treatment designed to produce a wave of DNA synthesis at the time of initiation leads to an even greater yield of tumours and nodules after promotion. This effect of phenobarbitone does not appear to be directly related to its ability to induce enzyme activity in the liver because lower doses of phenobarbitone (100 micrograms/ml or less) did not promote tumour development in spite of being adequate for the induction of cytochrome P-450 and associated enzyme activity. A similar incidence of hepatocellular carcinoma was found in both the groups given DMN and the top dose of Na phenobarbitone (1000 micrograms/ml) whether or not they had been given the dietary pretreatment. However, hyperplastic nodules were seen only in the diet pre-treated group. This is discussed in relation to the hypothesis that hyperplastic nodules are precursors of hepatic carcinoma.

Full text

PDF
131

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Butler W. H., Hempsall V., Stewart M. G. Histochemical studies on the early proliferative lesion induced in the rat liver by aflatoxin. J Pathol. 1981 Apr;133(4):325–340. doi: 10.1002/path.1711330405. [DOI] [PubMed] [Google Scholar]
  2. Butler W. H. Long-term effects of phenobarbitone-Na on male Fischer rats. Br J Cancer. 1978 Mar;37(3):418–423. doi: 10.1038/bjc.1978.62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Goldsworthy T., Campbell H. A., Pitot H. C. The natural history and dose-response characteristics of enzyme-altered foci in rat liver following phenobarbital and diethylnitrosamine administration. Carcinogenesis. 1984 Jan;5(1):67–71. doi: 10.1093/carcin/5.1.67. [DOI] [PubMed] [Google Scholar]
  4. Kitagawa T., Sugano H. Enhancing effect of phenobarbital on the development of enzyme-altered islands and hepatocellular carcinomas initiated by 3'-methyl-4-(dimethylamino) azobenzene or diethylnitrosamine. Gan. 1978 Oct;69(5):679–687. [PubMed] [Google Scholar]
  5. Marshall W. J., McLean A. E. The effect of oral phenobarbitone on hepatic microsomal cytochrome P-450 and demethylation activity in rats fed normal and low protein diets. Biochem Pharmacol. 1969 Jan;18(1):153–157. doi: 10.1016/0006-2952(69)90020-3. [DOI] [PubMed] [Google Scholar]
  6. McDanell R. E., McLean A. E. Differences between small and large intestine and liver in the inducibility of microsomal enzymes in response to stimulation by phenobarbitone and betanaphthoflavone in the diet. Biochem Pharmacol. 1984 Jun 15;33(12):1977–1980. doi: 10.1016/0006-2952(84)90558-6. [DOI] [PubMed] [Google Scholar]
  7. McLean A. E., Day P. A. The effect of diet on the toxicity of paracetamol and the safety of paracetamol-methionine mixtures. Biochem Pharmacol. 1975 Jan 1;24(1):37–42. doi: 10.1016/0006-2952(75)90310-x. [DOI] [PubMed] [Google Scholar]
  8. McLean A. E., Smith M., Driver H. E. Liver tumours after single dose dimethylnitrosamine, low and high protein diet, and phenobarbitone. Carcinogenesis. 1982;3(6):707–709. doi: 10.1093/carcin/3.6.707. [DOI] [PubMed] [Google Scholar]
  9. Peraino C., Fry R. J., Staffeldt E. Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. Cancer Res. 1971 Oct;31(10):1506–1512. [PubMed] [Google Scholar]
  10. Peraino C., Staffeldt E. F., Haugen D. A., Lombard L. S., Stevens F. J., Fry R. J. Effects of varying the dietary concentration of phenobarbital on its enhancement of 2-acetylaminofluorene-induced hepatic tumorigenesis. Cancer Res. 1980 Sep;40(9):3268–3273. [PubMed] [Google Scholar]
  11. Rossi L., Ravera M., Repetti G., Santi L. Long-term administration of DDT or phenobarbital-Na in Wistar rats. Int J Cancer. 1977 Feb 15;19(2):179–185. doi: 10.1002/ijc.2910190207. [DOI] [PubMed] [Google Scholar]
  12. Solt D. B., Medline A., Farber E. Rapid emergence of carcinogen-induced hyperplastic lesions in a new model for the sequential analysis of liver carcinogenesis. Am J Pathol. 1977 Sep;88(3):595–618. [PMC free article] [PubMed] [Google Scholar]
  13. Tatematsu M., Shirai T., Tsuda H., Miyata Y., Shinohara Y., Ito N. Rapid production of hyperplastic liver nodules in rats treated with carcinogenic chemicals: a new approach for an in vivo short-term screening test for hepatocarcinogens. Gan. 1977 Aug;68(4):499–507. [PubMed] [Google Scholar]

Articles from British journal of experimental pathology are provided here courtesy of Wiley

RESOURCES