Summary
Hyperplasia of the rat liver can be induced by cyproterone acetate (CPA). The fate of this hyperplasia after cessation of CPA treatment has been studied and the following findings were obtained:
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1.
Liver DNA content decreased by about 25% within a few days after CPA withdrawal.
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2.
In histological sections some hepatocytes showed degenerative changes. Among these, small membrane bounded bodies (“apoptotic bodies”; ABs) with or without chromatin were most numerous. Their incidence coincided with the phase of DNA elimination. Inflammatory reactions were not observed.
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3.
Their small size and occurrence in clusters suggests that many of these ABs are formed by fragmentation of dying hepatocytes.
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4.
Liver DNA was prelabelled with3H-thymidine. Autoradiographic evaluation showed that many hepatocytes contained labelled nuclei, but unlabelled ABs. This finding strongly suggests that ABs, after the fragmentation stage, can be phagocytized by intact hepatocytes. About 80% of all ABs were found within hepatocytes.
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5.
Extracellular ABs (early stage) contained no or very few active lysosomes. Intracellular ABs were sometimes surrounded by lysosomes, while others were in various stages of digestion. These observations suggest that the lysosomes of the phagocytizing hepatocytes degrade intracellular ABs, whereas intraapoptotic lysosomes seem to be inactive until the late stages of this degradation.
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6.
Hepatocytes that did not replicate during CPA-induced liver growth appear to die off preferentially after CPA withdrawal.
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7.
Retreatment with CPA greatly reduced the number of ABs within 4 h. Phenobarbital, another stimulus of liver growth, had the same effect.
These findings suggest that the present type of cell death can be inhibited by growth stimuli and is therefore a controlled event serving to eliminate an excess of cells, rather than a manifestation of toxic injury to hepatocytes. The findings also suggest that this type of cell death and elimination is a rapid process completed within a few hours.
It is concluded that cell death under the present experimental conditions probably occurs through apoptosis.
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Abbreviations
- CPA:
-
cyproterone acetate
- AB:
-
apoptotic body
- b.w.:
-
body weight
- PB:
-
phenobarbital
References
Argyris TS, Magnus DR (1968) The stimulation of liver growth and demethylase activity following phenobarbital treatment. Dev Biol 17:187–201
Bolender P, Weibel E (1973) A morphometric study of the removal of phenobarbital-induced membranes from hepatocytes after cessation of treatment. J Cell Biol 56:746–761
Bursch W, Lauer B, Timmermann-Trosiener T, Barthel G, Schuppler J, Schulte-Hermann R (1984) Controlled cell death (apoptosis) of normal and putative preneoplastic cells in rat liver following withdrawal of tumor promoters. Carcinogenesis 5:453–458
Columbano A, Ledda-Columbano GM, Coni G, Faa G, Liguori C, Santa-Cruz G and Pani P (1985) Occurrence of Cell Death (Apoptosis) during the involution of liver hyperplasia Lab Invest 52:670–675
Conney AH, Davison C, Gastel R, Burns JJ (1960) Adaptive increases in drug-metabolizing enzymes induced by phenobarbital and other drugs. J Pharmacol Exp Ther 130:1–8
Crampton RF, Gray TJB, Grasso P, Parke DV (1977) Long-term studies on chemically induced liver enlargement in the rat. I. Sustained induction of microsomal enzymes with absence of liver damage on feeding phenobarbitone or butylated hydroxytoluene. Toxicology 7:289–306
Deter RL (1971) Quantitative characterization of dense body, autophagic vacuole and acid phosphatase-bearing particle populations during the early phases of glucagon-induced autophagy in rat liver. J Cell Biol 48:473–489
Duke RC, Chervenak R, Cohen JG (1983) Endogenous endonuclease-induced DNA fragmentation: A early event in cell-mediated cytolysis. Proc Natl Acad Sci [USA] 80:6361–6365
Farber JA, Ei-Mofty SK (1975) The biochemical pathology of liver cell necrosis. Am J Pathol 81:237–250
Hendry JH, Potten CS, Chadwick C, Bianchi M (1982) Cell death (apoptosis) in the mouse intestine after low doses: effects of dose rate, 14,7 MeV neutrons and 600 MeV maximum energy neutrons. Int J Radiat Biol 42:611–620
Ferguson DJP, Anderson TJ (1981) Morphological evaluation of cell turnover in relation to the menstrual cycle in the “resting” human breast. Br J Cancer 44:177–181
Kerr JF (1971) Shrinkage necrosis: a distinct mode of cellular death. J Pathol 105:13–19
Kerr JFR, Searle J (1973) Deletion of cells by apoptosis during castration induced involution of rat prostate. Virchows Arch [Cell Pathol] 13:87–102
Levine WG, Ord MG, Stocken LA (1977) Some biochemical changes associated with Nafenopin induced liver growth in the rat. Biochem Pharmacol 26:939–942
Pearse AGE (1961) Histochemistry, theoretical and applied. Second edition; J& A Churchill LTD, London
Pfeifer U (1982) Kinetic and subcellular aspects of hypertrophy and atrophy. Int Rev Exp Pathol 23:1–45
Recknagel RO (1967) Carbon tetrachloride hepatotoxicity. Pharmacol Rev 19:145–149
Schlicht I, Koransky W, Magour S, Schulte Hermann R (1968) Größe und DNS-Synthese der Leber unter dem Einfluß körperfremder Stoffe. Naunyn-Schmiedebergs Arch Pharmakol Exp Pathol 261:26–41
Schulte-Hermann R (1977) Two-stage control of cell proliferation induced in rat liver by α-hexachlorocyclohexane. Cancer Res 37:166–171
Schulte-Hermann R, Hoffmann V, Landgraf H (1980 a) Adaptive responses of rat liver to the gestagen and anti- androgen cyproterone acetate and other inducers. III. Cytological changes. Chem Biol Interact 31:301–311
Schulte-Hermann R, Hoffmann V, Parzefall W, Kallenbach M, Gerhardt A, Schuppler J (1980b) Adaptive responses of rat liver to the gestagen and anti- androgen cyproterone acetate and other inducers. II. Induction of growth. Chem Biol Interact 31:287–300
Stiens R, Helpap B (1981) Die Regression der Rattenprostata nach Kastration. Histologische, morphometrische und zellkinetische Untersuchungen unter Berücksichtigung der Apoptose. Pathol Res Pract 172:73–87
Taper HS (1979) Evaluation of the validity of the histochemical lead nitrate technique for alkaline and acid deoxyribonuclease. J Histochem Cytochem 27:1483–1490
Trump BF, Berezesky IK, Osornio-Vargas AR (1981) Cell death and disease process. The role of calcium. In: Bowen ID, Lockshin RA (eds) Cell death in biology and pathology, Chapmann and Hall, London, New York
Wyllie AH (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284:555–556
Wyllie AH (1981) Cell death: a new classification separating apoptosis from necrosis. In: Bowen ID, Lockshin RA (eds) Cell death in biology and pathology. Chapmann and Hall, London, New York
Wyllie AH, Kerr JFR, Currie AR (1980) Cell death: the significance of apoptosis. Int Rev Cytol 68:251–306
Wyllie AR, Morris RG, Smith AL, Dunlop D (1984) Chromatin cleavage in apoptosis: association with condensed chromatin morphology and dependence of macromolecular synthesis. J Pathology 35:563–573
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Bursch, W., Taper, H.S., Lauer, B. et al. Quantitative histological and histochemical studies on the occurrence and stages of controlled cell death (apoptosis) during regression of rat liver hyperplasia. Virchows Archiv B Cell Pathol 50, 153–166 (1986). https://doi.org/10.1007/BF02889898
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DOI: https://doi.org/10.1007/BF02889898