A review of drug-induced lysosomal disorders of the liver in man and laboratory animals

Schneider, P. M.; Короленко, Т. А.; Busch, Ulrich

doi:10.1002/(sici)1097-0029(19970215)36:4<253::aid-jemt4>3.0.co;2-n

Cited by 72 publications

(26 citation statements)

References 95 publications

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“…Lysosomotropic agents, including particles, have been known for several decades to cause lysosomal dysfunction and associated toxicities of lung, liver and kidney [4,54]. Consequently, lysosomal dysfunction may be a common outcome of nanoparticle exposure since, as described above, nanoparticles are commonly sequestered within the lysosomal compartment.…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, lysosomal dysfunction may be a common outcome of nanoparticle exposure since, as described above, nanoparticles are commonly sequestered within the lysosomal compartment. Additionally, nanoparticles have properties of substances known to cause lysosomal disorders [54,55], including enzyme inhibiting ability [56,57] and biopersistence. Correspondingly, many researchers have observed nanomaterial-induced lysosomal dysfunction (see Table 1).…”

Section: Introductionmentioning

confidence: 99%

“…In further support of cationic PAMAM dendrimer interaction with the autophagy pathway, liver lesions observed in mice treated intraperitoneally (i.p.) with cationic PAMAM dendrimers in a separate study had histological features typical of lysosomal disorders observed with polycationic drugs, including vacuolization [54,107,108]. …”

Section: Introductionmentioning

confidence: 99%

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Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity

2012

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The study of the potential risks associated with the manufacture, use, and disposal of nanoscale materials, and their mechanisms of toxicity, is important for the continued advancement of nanotechnology. Currently, the most widely accepted paradigms of nanomaterial toxicity are oxidative stress and inflammation, but the underlying mechanisms are poorly defined. This review will highlight the significance of autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity. Most endocytic routes of nanomaterial cell uptake converge upon the lysosome, making the lysosomal compartment the most common intracellular site of nanoparticle sequestration and degradation. In addition to the endo-lysosomal pathway, recent evidence suggests that some nanomaterials can also induce autophagy. Among the many physiological functions, the lysosome, by way of the autophagy (macroautophagy) pathway, degrades intracellular pathogens, and damaged organelles and proteins. Thus, autophagy induction by nanoparticles may be an attempt to degrade what is perceived by the cell as foreign or aberrant. While the autophagy and endo-lysosomal pathways have the potential to influence the disposition of nanomaterials, there is also a growing body of literature suggesting that biopersistent nanomaterials can, in turn, negatively impact these pathways. Indeed, there is ample evidence that biopersistent nanomaterials can cause autophagy and lysosomal dysfunctions resulting in toxicological consequences.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity

2012

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“…Therefore, any method able to recognize the presence of a positive charge and a lipophilic moiety in the drug is able to produce reasonably good predictions and, not surprisingly, these models are in the catalogue of models applied in the pharmaceutical industry with good results. However, since not all CADs induce phospholipidosis and some drug inducing PL are not CADs [42,43], even in this case improvements can still be made. Furthermore, there are many other toxicological outcomes, such as hepatotoxicity, that depend on numerous diverse known biological mechanisms [44–49] and probably many more unknown ones.…”

Section: Improving Toxicity Prediction—the Etox Projectmentioning

confidence: 99%

Inroads to Predict in Vivo Toxicology—An Introduction to the eTOX Project

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Heard

et al. 2012

IJMS

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There is a widespread awareness that the wealth of preclinical toxicity data that the pharmaceutical industry has generated in recent decades is not exploited as efficiently as it could be. Enhanced data availability for compound comparison (“read-across”), or for data mining to build predictive tools, should lead to a more efficient drug development process and contribute to the reduction of animal use (3Rs principle). In order to achieve these goals, a consortium approach, grouping numbers of relevant partners, is required. The eTOX (“electronic toxicity”) consortium represents such a project and is a public-private partnership within the framework of the European Innovative Medicines Initiative (IMI). The project aims at the development of in silico prediction systems for organ and in vivo toxicity. The backbone of the project will be a database consisting of preclinical toxicity data for drug compounds or candidates extracted from previously unpublished, legacy reports from thirteen European and European operation-based pharmaceutical companies. The database will be enhanced by incorporation of publically available, high quality toxicology data. Seven academic institutes and five small-to-medium size enterprises (SMEs) contribute with their expertise in data gathering, database curation, data mining, chemoinformatics and predictive systems development. The outcome of the project will be a predictive system contributing to early potential hazard identification and risk assessment during the drug development process. The concept and strategy of the eTOX project is described here, together with current achievements and future deliverables.

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“…Degradation of endocytosed extracellular matter and plasma membrane components is a complex process that involves selective membrane fusion, protein and lipid sorting and degradation, and absorption of the products of digestion [3, 4]. LSDs occur due to mutations in genes that code for components of the cellular endocytic machinery, or they can be caused by environmental influences such as toxic metals or drugs [5–7]. LSDs caused by gene mutations result in improperly delivered, structurally dysfunctional, or acutely inhibited lysosomal digestive enzymes; in some cases LSDs-causing mutations affect absorption of the products of digestion.…”

Section: Lysosomal Storage Diseases As a Model For The Integrative Fumentioning

confidence: 99%

Aberrant Ca2+ handling in lysosomal storage disorders

et al. 2010

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Lysosomal storage diseases (LSDs) are caused by inability of cells to process the material captured during endocytosis. While they are essentially diseases of cellular "indigestion", LSDs affect large number of cellular activities and, as such, they teach us about the integrative function of the cell, as well as about the gaps in our knowledge of the endocytic pathway and membrane transport. The present review summarizes recent findings on Ca 2+ handling in LSDs and attempts to identify the key questions on alterations inCa 2+ signaling and membrane transport in this group of diseases, answers to which may lie in delineating the cellular pathogeneses of LSDs. Lysosomal storage diseases as a model for the integrative function of the cellLysosomal storage diseases (LSDs) area diverse set of conditions that impair the uptake, sorting, or digestion of the material captured by cells during endocytosis or claimed by autophagy [1,2]. Degradation of endocytosed extracellular matter and plasma membrane components is a complex process that involves selective membrane fusion, protein and lipid sorting and degradation, and absorption of the products of digestion [3,4]. LSDs occur due to mutations in genes that code for components of the cellular endocytic machinery, or they can be caused by environmental influences such as toxic metals or drugs [5][6][7]. LSDs caused by gene mutations result in improperly delivered, structurally dysfunctional, or acutely inhibited lysosomal digestive enzymes; in some cases LSDs-causing mutations affect absorption of the products of digestion. Additionally, recently accumulated data suggests impaired membrane flow in the endocytic pathway, whether directly or indirectly induced by the genetic mutations, as a contributing factor in LSDs pathogenesis [8].Although they are rarely discussed in the context of LSDs, chemically-induced dysregulated lysosomal function due to acute poisoning or chronic buildup of inhibitors (such as in irondependent lipofuscin buildup in aging cells [9,10], and, perhaps, in Mucolipidosis type IV [11]), share elements of causality as well as cellular and clinical manifestations with the "genetically-induced" LSDs.The inability of cells affected by LSDs to properly handle endocytosed material results in buildup of storage bodies, which are malformed endocytic organelles filled with undigested or © 2009 Elsevier Ltd. All rights reserved.Address correspondence to: Kirill Kiselyov, Department of Biological Sciences, University of Pittsburgh, 519 Langley Hall, 4249 Fifth Ave, Pittsburgh, PA, 15260, USA. Kiselyov@pitt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal d...

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A review of drug-induced lysosomal disorders of the liver in man and laboratory animals

Cited by 72 publications

References 95 publications

Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity

Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity

Inroads to Predict in Vivo Toxicology—An Introduction to the eTOX Project

Aberrant Ca2+ handling in lysosomal storage disorders

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