Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Age-, sex-, and strain-dependent differences in the induction of enzyme-altered islands in rat liver by diethylnitrosamine

  • 24 Accesses

  • 29 Citations


The formation of foci with loss of ATPase and emergence of γ-GTase was studied histochemically in livers of male and female Wistar and Sprague-Dawley rats of 3–4 and 6–7 weeks of age, respectively, after application of diethylnitrosamine. A single dose of 8 mg/kg body weight induced a considerable island formation in weanlings of both sexes. Island induction in adults was observed only after repeated application. No difference in island size and number was observed with the exception of greater island size in Sprague-Dawley females.

Sex-dependent differences in susceptibility to island induction were observed in weanlings, females being more sensitive than males and Sprague-Dawley females being the most sensitive of all. No correlation was seen between monooxygenase activity and the extent of island formation. The coincidence of ATPase-deficiency and emergence of γ-GTase was highest in Sprague-Dawley females. The importance of this result in respect to cancer formation is discussed. Weanling Sprague-Dawley females seemed to be the most suitable for use in a screening test system for chemical carcinogenicity, especially for testing low doses or weak carcinogens.

This is a preview of subscription content, log in to check access.



adenosine triphosphatase (E.C.




γ-glutamyltranspeptidase (E.C.


  1. Appel KE, Schwarz M, Rickart R, Kunz W (1979) Influences of inducers and inhibitors of the microsomal monooxygenase system on the alkylating intensity of dimethylnitrosamine in mice. J Cancer Res Clin Oncol 94:47–61

  2. Bannasch P, Hesse J, Angerer H (1974) Hepatozelluläre Glykogenose und die Genese sogenannter hyperplastischer Knoten in der Thioacetamid-vergifteten Rattenleber. Virchows Arch [Cell Pathol] 17:29–50

  3. Börner P, Gössner W (1968) Enzymhistochemische Untersuchungen der Adenosintriphosphatase, der alkalischen und sauren Phosphatase sowie der Succinodehydrogenase im Leberparenchym der Ratte während der Einwirkung des Cancerogens Diäthylnitrosamin. Z Naturforsch 23b:1085–1091

  4. El Defrawy el Masry, S, Cohen GM, Mannering GJ (1974) Sex-dependent differences in drug metabolism in the rat. I. Temporal changes in the microsomal drug-metabolizing system of the liver during sexual maturation. Drug Metab Dispos 2:267–278

  5. Farber E (1973) Hyperplastic liver nodules. Meth Cancer Res 7:345–375

  6. Farber E (1976) Hyperplastic areas, hyperplastic nodules and hyperbasophilic areas as putative precursor lesions. Cancer Res. 36:2532–2533

  7. Friedrich-Freksa H, Papadopulu C, Gössner W (1969) Histochemische Untersuchungen der Cancerogenese in der Rattenleber nach zeitlich begrenzter Verabfolgung von Diäthylnitrosamin. Z Krebsforsch 72:240–253

  8. Gielen JE, Van Cantfort J, Kremers P (1976) Genetic and hormonal regulation of steroid hydroxylases and drug metabolizing enzymes in rat liver. Arch Toxicol 36:255–266

  9. Gössner W, Friedrich-Freksa H (1964) Histochemische Untersuchungen über die Glucose-6-phosphatase in der Rattenleber während der Cancerisierung durch Nitrosamine. Z Naturforsch 19b:862–863

  10. Kalengayi M, Ronchi G, Desmet VJ (1975) Histochemistry of gamma glutamyl transpeptidase in rat liver during Aflatoxin B1-induced carcinogenesis. J Natl Cancer Inst 55:579–588

  11. Kato R (1974) Sex-related differences in drug metabolism. Drug Metab Rev 3:1–32

  12. Kitagawa T (1971) Histochemical analysis of hyperplastic lesions and hepatomas of the liver of rats fed 2-fluorenylacetamide. Gann 62:207–216

  13. Kunz W, Schaude G, Thomas C (1969) Die Beeinflussung der Nitrosamincarcinogenese durch Phenobarbital und Halogenkohlenwasserstoffe. Z Krebsforsch 72:291–304

  14. Kunz W, Appel KE, Rickart R, Schwarz M, and Stöckle G (1978) Enhancement and inhibition of carcinogenic effectiveness of nitrosamines. In: Remmer H, Bolt HM, Bannasch P, Popper H (eds) Primary liver tumors. MTP Press, Lancaster, pp 261–283

  15. Lojda Z, Gossrau R, Schiebler TH (1976) Enzymhistochemische Methoden. Springer, Berlin Heidelberg New York, pp 182–184

  16. Magee PN, Barnes JM (1967) Carcinogenic nitroso compounds. Adv Cancer Res 10:163–246

  17. Magour S, Nievel JG (1971) Effect of inducers of drug-metabolizing enzymes on diethylnitrosamine metabolism and toxicity. Biochem J 123:8P-9P

  18. Nash T (1953) The colorimetric estimation of formaldehyde by means of the Hantzsch reaction. Biochem J 55:416–421

  19. Pegg AE (1977) Formation and metabolism of alkylated nucleosides: Possible role in carcinogenesis by nitroso compounds and alkylating agents. Adv Cancer Res 25:195–259

  20. Pitot HC, Barsness L, Goldsworthy T, Kitagawa T (1978) Biochemical characterisation of stages of hepatocarcinogenesis after a single dose of diethylnitrosamine. Nature 271:456–458

  21. Rohr H, Oberholzer M, Bartsch G, Keller M (1976) Morphometry in experimental pathology: Methods, baseline data, and applications. Int Rev Exp Pathol 15:233–325

  22. Schauer A, Kunze UE (1968) Enzymhistochemische und autoradiographische Untersuchungen während der Cancerisierung der Rattenleber mit Diäthylnitrosamin. Z Krebsforsch 70:252

  23. Scherer E, Emmelot P (1975) Foci of altered liver cells induced by a single dose of diethylnitrosamine and partial hepatectomy: Their contribution to hepatocarcinogenesis in the rat. Eur J Cancer 11:145–154

  24. Scherer E, Emmelot P (1976) Kinetics of induction and growth of enzyme-deficient islands involved in hepatocarcinogenesis. Cancer Res. 36:2544–2554

  25. Scherer E, Hoffmann M (1971) Probable clonal genesis of cellular islands induced in rat liver by diethylnitrosamine. Eur J Cancer 7:369–371

  26. Schieferstein G, Pirschel J, Frank W, Friedrich-Freksa H (1974) Quantitative Untersuchungen über den irreversiblen Verlust zweier Enzymaktivitäten in der Rattenleber nach Verfütterung von Diäthylnitrosamin. Z Krebsforsch 82:191–208

  27. Schoental R (1974) Carcinogenicity as related to age. Ann Rev Pharmacol 14:185–204

  28. Short CR, Kinden DA, Stith R (1976) Fetal and neonatal development of the microsomal monooxygenase system. Drug Metab Rev 5:1–42

  29. Solt D, Farber E (1977) Persistence of carcinogen-induced initiated hepatocytes in liver carcinogenesis. Proc Am Assoc Cancer Res 18:52

  30. Wachstein M, Meisel E, Niedzwiedz A (1960) Histochemical demonstration of mitochondrial adenosine triphosphatase with the lead adenosine triphosphatase technique. J Histochem Cytochem 8:387–388

  31. Weibel ER (1969) Stereological priciples for morphometry. Int Rev Cytol 26:235–302

  32. Wolff T (1978) In vitro inhibition of monooxygenase dependent reactions by organic solvents. In: Fouts JR, Gut I (eds) Industrial and environmental xenobiotics. Excerpta Medica. Amsterdam Oxford, pp 196–199

  33. Wolff T, Hesse S (1977) Species differences of mixed function oxidase induction between rabbits and rats after pretreatment with polychlorinated biphenyls (PCBs). Biochem Pharmacol 26:783–787

Download references

Author information

Correspondence to E. Deml.

Additional information

Supported by the Deutsche Forschungsgemeinschaft

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Deml, E., Oesterle, D., Wolff, T. et al. Age-, sex-, and strain-dependent differences in the induction of enzyme-altered islands in rat liver by diethylnitrosamine. J Cancer Res Clin Oncol 100, 125–134 (1981). https://doi.org/10.1007/BF00403362

Download citation

Key words

  • Enzyme-altered islands
  • Differences in induction rate
  • Diethylnitrosamine