Elsevier

Biochemical Pharmacology

Volume 31, Issue 23, 1 December 1982, Pages 3795-3799
Biochemical Pharmacology

Studies on the mechanism of phospholipid storage induced by amantadine and chloroquine in Madin Darby canine kidney cells

https://doi.org/10.1016/0006-2952(82)90295-7Get rights and content

Abstract

Previous studies suggested that hepatic lipidosis caused by cationic amphiphilic drugs in rats is related to the capacity of these drugs to concentrate in liver lysosomes. These drugs inhibit lysosomal phospholipases, causing phospholipid accumulation. Amantadine, an inhibitor of influenza A virus replication, is a cationic amphiphilic drug which concentrates in the lysosomes of the Madin Darby canine kidney (MDCK) cell. In the present study, amantadine and chloroquine were shown to inhibit soluble lysosomal phospholipases isolated from MDCK cell in. vitro. Both amantadine and chloroquine concentrated in MDCK cell lysosomes. These drugs caused phospholipid storage in cultured MDCK cells, and the amounts of the respective agents required to cause phospholipid storage correlated with the capacities of the agents to inhibit lysosomal phospholipases. The mechanisms involved in this phenomenon are discussed, and a three-step hypothesis is presented predicting which agents will cause phospholipidosis.

References (21)

  • Y. Matsuzawa et al.

    J. Lipid Res.

    (1980)
  • Y. Matsuzawa et al.

    J. biol. Chem.

    (1980)
  • K.Y. Hostetler et al.

    Biochem. Pharmac.

    (1981)
  • D.D. Richman et al.

    Virology

    (1981)
  • O.H. Lowry et al.

    J. biol. Chem.

    (1951)
  • T.G. Warner et al.

    J. Lipid Res.

    (1977)
  • J. Folch et al.

    J. biol. Chem.

    (1957)
  • M. Hollemans et al.

    Biochim. biophys. Acta

    (1981)
  • A. Yamamoto et al.

    J. Biochem., Tokyo

    (1971)
  • A. Yamamoto et al.

    J. Biochem., Tokyo

    (1971)
There are more references available in the full text version of this article.

Cited by (48)

  • Evaluation and validation of multiple cell lines and primary mouse macrophages to predict phospholipidosis potential

    2011, Toxicology in Vitro
    Citation Excerpt :

    Drug-induced PLD is generally associated with amine-containing cationic amphiphilic drugs (CADs) that are protonated and trapped in the acidic milieu of lysosomes causing significant tissue accumulation of drug (Kaufmann and Krise, 2007; Yokogawa et al., 2002). Although the molecular mechanism for PLD is not fully established, binding of CADs to lysosomal lipids can interfere with phospholipase activity by disrupting membrane fluidity (Grabner, 1987) or decreasing enzymatic activity, as has been demonstrated with phospholipase A, C, (Hostetler and Matsuzawa, 1981; Hostetler and Richman, 1982; Matsuzawa and Hostetler, 1980) and sphingomyelinase (Yoshida et al., 1985). A mouse model for sphingomyelinase deficiency or Niemann–Pick disease (Nakashima et al., 1984) accumulate sphingomyelin in target organs resulting in lesions that are characteristically reminiscent of PLD.

  • Effect of co-administration of fluoxetine and amantadine on immunoendocrine parameters in rats subjected to a forced swimming test

    2009, Pharmacological Reports
    Citation Excerpt :

    Indeed, treatment of isolated mouse spleen T cells, but not accessory cells, with AMA inhibited the proliferative response to Con A. Moreover, it was demonstrated that AMA affected CD8+ cells (suppressor/cytotoxic cells), but had no effect on CD4+ ones [9]. The possible AMA-mediated modes of action on the cascade of events involved in the activation and proliferation of T lymphocytes are: a) the hydrophobic bonding of AMA to membrane lipids (steric modification of cellular receptors), and b) the inhibitory activity of AMA on protein synthesis, phospholipid metabolism [8] and soluble phos-pholipases A and C [28]. In vitro studies have shown a direct inhibitory effect of AMA (used in relatively high doses) on lymphocyte proliferation [10].

  • Iatrogenic Phospholipidosis Mimicking Fabry Disease

    2006, American Journal of Kidney Diseases
    Citation Excerpt :

    Iatrogenic phospholipidosis has been reported in association with several drugs; the most common are chloroquine and amiodarone.14-16 Chloroquine is a weak base that becomes concentrated within lysosomes and inhibits key lysosomal enzymes, including α-galactosidase A, in addition to cathepsin, acid hydrolase, and phospholipases.14,17-22 Because of similarities in chemical structure, it is reasonable to assume that hydroxychloroquine causes iatrogenic phospholipidosis in a manner similar to chloroquine.

  • Chloroquine-induced phospholipidosis of the kidney mimicking fabry's disease: Case report and review of the literature

    2003, Human Pathology
    Citation Excerpt :

    The resulting increase in lysosomal pH is an important mechanism in the inactivation of lysosomal enzymes and impairment of degradative capacity.33-35 Chloroquine thereby inhibits the activity of various enzymes, including cathepsin, acid hydrolase,36-38 phospholipase,39,40 and other lysosomal enzymes,41 and also of transport ATPases42 and glutamate-dehydrogenase.43 Chloroquine has also been reported to induce morphological and functional changes in mitochondria.44

View all citing articles on Scopus
View full text