Abstract
Several substances with lysosomotropic activity were investigated in toxicological studies. AR-L 115 BS (sulmazol, a cardiotonic agent) was tested on beagle dogs; HX-CH 44 BS (a β-blocker) and SX-AB 1316 SE (an antithrombotic agent) were tested on rats, and AF-CX 1325 XX (an antiepileptic agent) was tested on both rats and beagle dogs. All organ systems were examined morphologically by light and/or electron microscopy. When an increase in the number of lysosomes occurred this was confirmed by the pigment scheme according to Krutsay (1971) as well as by the detection of acid phosphatase and compared with earlier histochemical results. At higher dosages, all substances caused very marked proliferation of lysosomes in the liver and/or kidneys. HX-CH 44 BS also caused such proliferation in striated muscles and in the lungs. A brown discolouration of the kidneys was found with sulmazol and AF-CX 1325 XX. This finding corresponded to the microscopically detectable occurrence of numerous lipofuscin granules. The reticulum cells in the lymph nodes of dogs were also affected by AF-CX 1325 XX. It is concluded that the proliferation of lysosomes in various organs after administration of the above-mentioned substances is due to an excess of substance. The increased substance in the body is then stored in the lysosomes. With HX-CH 44 BS, lysosomal autodigestion of mitochondria in the skeletal musculature and in the alveolar macrophages of the lungs was found. The selective lysosomal incorporation of mitochondria has not been described up to now and in our opinion, this constitutes a special feature. The results otherwise largely correspond to those already described in the literature. Systemic phospholipidosis such as occurs with some other substances was not detectable. The incorporation of the substance causes several types of lysosomal inclusion. Uptake of the substance in lysosomes either leads to overt autodigestion of organelles such as mitochondria (HX-CH 44 BS) or peroxisomes or to residual lysosomes of dense structure which histochemically resemble lipofuscin. SX-AB 1316 SE serves as an example of a substance which is stored directly by lysosomes in crystalline form. Above all, in the liver the substance is taken up not only by the sinusoidal stellate cells but also by hepatocytes.
Similar content being viewed by others
References
Altmann HW (1980) Drug-induced liver reactions. A morphological approach. In: Grundmann E (ed) Drug-induced pathology. Springer, Berlin Heidelberg New York
Ardenne M von, Krüger W (1979) Local tissue hyperacidification and lysosomes. In: Dingle JT, Jaques PJ, Shaw IH (eds) Lysosomes in applied biology and therapeutics, Vol 6. North-Holland Publishing Company, Amsterdam New York Oxford, pp 161–194
Bancroft JD, Stevens A (1982) Theory and practice of histological techniques, 2nd edn. Churchill Livingstone, Edinburgh London Melbourne New York
Beck F, Lloyd JB (1975) Histochemistry and electron microscopy of lysosomes. In: Dingle JT, Fell HB (eds) Lysosomes in biology and pathology, vol 2. North-Holland Publishing Company, Amsterdam London and American Elsevier Publishing Co. Inc., New York, pp 567–599
Bird JWC (1975) Skeletal muscle lysosomes. In: Dingle JT, Dean RT (eds) Lysosomes in biology and pathology, vol 4. North-Holland Publishing Company, Amsterdam Oxford and American Elsevier Publishing Co. Inc., New York
Bradford WD, Elchlepp JG, Arstila AU, Trump BF, Kinney TD (1969) Iron metabolism and cell membranes. Am J Pathol 56: 201–211
Bradley MO, Taylor VI, Armstrong MJ, Galloway SM (1987) Relationships among cytotoxicity, lysosomal breakdown, chromosome aberrations and DNA double-strand breaks. Mutat Res 189: 69–79
Coen H, Roels F, Cornelius A, Claeys A, Verpooten GA, De Broe ME (1988) Automated measurement of kidney lysosomes by light microscopy. Influence of cyclosporine treatment. Anal Quant Cytol Histol 10: 87–93
Cohn ZA, Fedorko ME (1975) The formation and fate of lysosomes. In: Dingle JT, Fell HB (eds) Lysosomes in biology and pathology, vol 1. North-Holland Publishing Company, Amsterdam London and American Elsevier Publishing Co. Inc., New York, pp 43–63
Cottier H (1980) Pathogenese. Ein Handbuch für die ärztliche Fortbildung, Vol 2. Springer, Berlin Heidelberg New York
Daems WTh, Wisse E, Brederoo P (1975) Electron microscopy of the vacuolar apparatus. In: Dingle JT, Fell HB (eds) Lysosomes in biology and pathology, vol 1. North-Holland Publishing Company, Amsterdam London and American Elsevier Publishing Co. Inc., New York
Davies P, Allison AC (1976) The secretion of lysosomal enzymes. In: Dingle JT, Dean RT (eds) Lysosomes in biology and pathology, vol 5. North-Holland Publishing Company, Amsterdam Oxford and American Elsevier Publishing Co. Inc., New York, pp 61–98
De Duve C (1975) The lysosome in retrospect. In: Dingle JT, Fell HB (eds) Lysosomes in biology and pathology, vol 1. North-Holland Publishing Company, Amsterdam London and American Elsevier Publishing Co. Inc., New York
De Duve C, Wattiaux R (1966) Functions of lysosomes. Annu Rev Physiol 28: 435–492
De Duve C, Pressman BC, Gianetto R, Wattiaux R, Appelmans F (1955) Tissue fractionation studies. Biochem J 60: 604–617
Dingle JT (ed) (1973) Lysosomes in biology and pathology, vol 3. North-Holland Publishing Company, Amsterdam London and American Elsevier Publishing Co. Inc., New York
Dingle JT (1975) The extracellular secretion of lysosomal enzymes. In: Dingle JT, Fell HB (eds) Lysosomes in biology and pathology, vol 2. North-Holland Publishing Company, Amsterdam London and American Elsevier Publishing Co. Inc., New York, pp 421–436
Dingle JT, Dean RT (eds) (1975) Lysosomes in biology and pathology vol 4. North-Holland Publishing Company, Amsterdam Oxford and American Elsevier Publishing Co. Inc., New York
Dingle JT, Dean RT (eds) (1976) Lysosomes in biology and patholog vol 5. North-Holland Publishing Company, Amsterdam Oxford and American Elsevier Publishing Co. Inc., New York
Dingle JT, Fell HB, ed (1975 a) Lysosomes in biology and pathology, vol 1. North-Holland Publishing Company, Amsterdam London and American Elsevier Publishing Co. Inc., New York
Dingle JT, Fell HB (eds) (1975 b) Lysosomes in biology and pathology. vol 2. North-Holland Publishing Company, Amsterdam London and American Elsevier Publishing Co. Inc., New York
Dingle JT, Jacques PJ, Shaw IH (eds) (1979) Lysosomes in applied biology and therapeutics, vol 6. North-Holland Publishing Company. Amsterdam New York Oxford
Dingle JT, Dean RT, Sly W (eds) (1984) Lysosomes in biology and pathology, vol 7. Elsevier, Amsterdam New York Oxford
Engel AG (1973) Vacuolar myopathies: multiple etiologies and sequential structural studies. In: The striated muscle; International Academy of Pathology, Monograph No. 12, Chapter 16. The Williams and Wilkins Company, Baltimore, Md, pp 301–341
Ericsson JLE (1975) Mechanism of cellular autophagy. In: Dingle JI. Fell HB (eds) Lysosomes in biology and pathology, vol 2. North-Holland Publishing Company, Amsterdam London and American Elsevier Publishing Co. Inc., New York, pp 345–394
Gebbia N, Leto G, Gagliano M, Tumminello FM, Rausa L (1985) Lysosomal alterations in heart and liver of mice treated with doxorubicin Cancer Chemother Pharmacol 15 [1]: 26–30
Gedigk P, Totovic V (1976) Lysosomen und Pigmente. Verh Dtsch Ges Path 60: 64–94
Gopinath C, Prentice DE, Lewis DJ (1987) Atlas of experimental toxicological pathology. In: Gresham GA (ed) Current histopathology vol 13. MTP Press Ltd, Lancaster Boston The Hague Dordrecht
Gordon AH (1973) The role of lysosomes in protein catabolism. In Dingle JT (ed) Lysosomes in biology and pathology, vol 3. North-Holland Publishing Company Amsterdam London and American Elsevier Publishing Co. Inc., New York, pp 89–137
Karabelnik D, Zbinden G (1975) Drug-induced cell reactions in rats II. chemical analysis of lipids stored in lungs and foam cells after treatment with chlorphentermine, 5-[p-(fluoren-9-ylidenemethyl) phenyl]-2-piperidineethanol (RMI, 10.393) and 1-chloramitriptyline Hoppe-Seyler's Z Physiol Chem 356: 1151–1160
Karabelnik D, Zbinden G (1976) Palmitic acid-1-14C incorporation and turnover in lung phospholipids of rats, treated with chlorphentermine RMI 10.393 and Ro 4-4318. Arch Toxicol 35: 163–174
Karabelnik D, Zbinden G, Baumgartner E (1974) Drug-induced foam cell reactions in rats. I. Histopathologic and cytochemical observations after treatment with chlorphentermine, RMI 10.393 and R0 4-4318. Toxicol Appl Pharmacol 27: 395–407
Kerr JFR (1973) Some lysosome functions in liver cells reacting to sublethal injury. In: Dingle JT (ed) Lysosomes in biology and pathol ogy, vol 3. North-Holland Publishing Company, Amsterdam London and American Elsevier Publishing Company, Inc., New York pp 365–394
Krutsay M (1971) Identifizierung von Pigmenten in Paraffinschnitten Zentralbl Allg Pathol 114: 374–376
Kumaratilake JS, Howell JM (1989) Lysosomes in the pathogenesis of liver injury in chronic copper poisoned sheep: an ultrastructural and morphometric study. J Comp Pathol 100: 381–390
Laberke HG (1980) Drug-associated nephropathy. Part II: Tubulo-inter stitial lesions. A: acute interstitial nephritis, nephro-toxic lesions analgesic nephropathy. In: Grundmann E (ed) Drug-induced pathology. Springer, Berlin Heidelberg New York
Langer KH (1976) Lysosomen und Heterophagie. Verh Dtsch Ges Pathol 60: 9–27
Lewis JC, Taylor RG, Ohta K (1988) Lysosomal alterations during coronary atherosclerosis in the pigeon: correlative cytochemical and three-dimensional HVEM/IVEM observations. Exp Mol Pathol 48: 103–115
Lüllmann HP, Lüllmann-Rauch R, Wassermann O (1973) Arzneimittelinduzierte Phospholipidspeicherkrankheit. Dtsch Med Wochenschr 98: 1616–1625
Lüllmann HP, Lüllmann-Rauch R, Wassermann O (1978) Lipidosis induced by amphiphilic cationic drugs. Biochem Pharmacol 27: 1103–1108
Lüllmann-Rauch R (1979) Drug-induced lysosomal storage disorders. In: Dingle JT, Jaques PJ, Shaw IH (eds) Lysosomes in applied biology and therapeutics, vol 6. North-Holland Publishing Company, Amsterdam New York Oxford
Macdonald RD, Engel AG (1970) Experimental chloroquine myopathy. J Neuropathol Exp Neurol 29: 479–499
Maunsbach AB (1966) The influence of different fixatives and fixation methods on the ultrastructure of rat kidney proximal tubule cells. I. Comparison of different perfusion fixation methods and of glutaraldehyde, formaldehyde and osmium tetroxide fixatives. J Ultrastruct Res 15: 242–282
Maunsbach AB (1975) Functions of lysosomes in kidney cells. In: Dingle JT, Fell HB (eds) Lysosomes in biology and pathology, vol 1. North-Holland Publishing Company, Amsterdam London and American Elsevier Publishing Co. Inc., New York
Novikoff AB, Podber E, Ryan J, Noe E (1953) Biochemical heterogeneity of the cytoplasmic particles isolated from rat liver homogenate. J Histochem Cytochem 1: 27–46
Novikoff AB, Beaufay H, De Duve C (1956) Electron microscopy of lysosome-rich fractions from rat liver. J Biophys Biochem Cytol 2: 179–184
Pfeifer U (1976) Lysosomen und Autophagie. Verh Dtsch Ges Pathol 60: 28–64
Phillips MJ, Poucell S, Patterson J, Valencia P (1987) The liver. An atlas and text of ultrastructural pathology. Raven Press, New York
Reddy JK, Rao MS, Qureshi SA, Reddy MK, Scarpelli DG, Lalwani ND (1984) Induction and origin of hepatocytes in rat pancreas. J Cell Biol 98: 2082–2090
Ridout RM, Wildenthal K, Decker RS (1986) Influence of agents that alter lysosomal function on fetal mouse hearts recovering from anoxia and substrate depletion. J Mol Cell Cardiol 18: 867–876
Roels F, Paulus G, De Broe ME (1984) Lysosomal modifications in human proximal tubule induced by aminoglycoside treatment: visualisation by light microscopical cytochemistry. Pathol Res Pract 179: 230–234
Sandritter W, Thomas C (1986) Histopathologie. Lehrbuch und Atlas für die Kurse der allgemeinen und experimentellen Pathologie. Thomas C (ed), 10th ed. Schattauer, Stuttgart New York
Schneider P (1973) Lysosomale Enzyme in der Niere des Hundes bei chronischer interstitieller Nephritis und Tubulonephrose. Beitr Path 148: 242–254
Schneider P, Ueberberg H (1982) Experimentelle Pigmentnephropathien und renale Speicherungsphänomene In: Baß R, Grosdanoff P, Hebold G, Stötzer H (eds) Zur Problematik der arzneimittel-bedingten Nephrotoxizität, AMI-Berichte, Institut für Arzneimittel des Bundesgesundheitsamtes, Dietrich Reimer Verl., Berlin
Schneider P, Pappritz G, Müller-Peddinghaus R, Bauer M, Lehmann H, Ueberberg H, Trautwein G (1980) Die Kaliumhydrogenphosphat-induzierte Nephropathie des Hundes. I. Pathogenese der Tubulus-atrophie. Vet Pathol 17: 699–719
Schneider P, Bauer M, Eckenfels A, Lehmann H, Lützen L, Ueberberg H (1981) Tierexperimentelle Untersuchung zur Verträglichkeit von AR-L 115 BS. Arzneimittelforschung 31: 226–232
Schneider P, Bauer M, Busch U, Meister H (1990) Experimental pancytopenia of the peripheral blood with granulocytopoietic bone marrow hyperplasia in the beagle-dog. Exp Pathol 38: 201–215
Sewell RB, Dillon C, Grinpukel S, Yeomans ND, Smallwood RA (1986) Pericanalicular location of hepatocyte lysosomes and effects of fasting: a morphometric analysis. Hepatology 6: 305–311
Silverblatt FJ, Kühn C (1979) Autoradiography of gentamycin uptake by the rat proximal tubule cell. Kidney Int 15: 335–345
Smith RE, Van Frank RM (1975) The use of amino acid derivates of 4-methoxy-β-naphthylamine for the assay and subcellular localization of tissue proteinases. In: Dingle JT, Dean RT (eds) Lysosomes in biology and pathology, vol 4. North-Holland Publishing Company, Amsterdam Oxford and American Elsevier Publishing Co. Inc., New York, pp 193–249
Spangler WL, Adelman RD, Conzelman GM Jr, Ishizaki G (1980) Gentamycin nephrotoxicity of the dog: sequential light and electron microscopy. Vet Pathol 17: 206–217
Szergo CM (1975) Lysosomal function in nucleocytoplastic communication. In: Dingle JT, Dean RT (eds) Lysosomes in biology and pathology, vol 4. North-Holland Publishing Company, Amsterdam Oxford and American Elsevier Publishing Co. Inc., New York, pp 385–477
Toskulkao C, Glinsukon T (1990) Hepatic mitochondrial function and lysosomal enzyme activity in ethanol-potentiated aflatoxin B1 hepatotoxicity. Toxicol Lett 52: 179–190
Vogler C, Rosenberg HS, Williams JC, Butler I (1987) Electron microscopy in the diagnosis of lysosomal storage diseases. Am J Med Genet Suppl 3: 243–255
Werb Z, Dingle JT (1976) Lysosomes as modulators of cellular functions. Influence on the synthesis and secretion of non-lysosomal materials. In: Dingle JT, Dean RT (eds) Lysosomes in biology and pathology, vol 5. North-Holland Publishing Company, Amsterdam Oxford and American Elsevier Publishing Co. Inc., New York
Author information
Authors and Affiliations
Additional information
Dedicated to Professor Gerhard Zbinden, MD, on the occasion of his retirement
Rights and permissions
About this article
Cite this article
Schneider, P. Drug-induced lysosomal disorders in laboratory animals: new substances acting on lysosomes. Arch Toxicol 66, 23–33 (1992). https://doi.org/10.1007/BF02307266
Issue Date:
DOI: https://doi.org/10.1007/BF02307266