Cellular uptake of aminoglycosides

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Abstract

Aminoglycosides exert their cytotoxic effect at three different locations: at the cell surface, in the cytosol, or in the nucleus. At the cell surface, aminoglycoside binding can cause temporary hearing loss, motor paralysis at the neuromuscular junction, ion wasting in kidneys, or analgesia in mechano- and nocioreceptors (touch and pain sensory cells). More severe and permanent cytotoxic events occur following aminoglycoside entry into the cell, via one or more transport mechanisms to cross the plasma membrane. Endocytosis is the most widely studied aminoglycoside uptake mechanism, but it remains uncertain whether this is receptor-mediated, non-specific fluid-phase mediated, or both; and if endocytotic uptake can lead directly to cytotoxidty. Endocytosis is a rate-limiting, temperature-dependent mechanism that does not account for the rapidity or temperature-independence of observed cytotoxic sequelae, including mitochondrial permeabilization, and toxic generation of reactive oxygen species. Aminoglycosides can also enter directly into the cytosol through ion channels in auditory and vestibular hair cells, kidney cells and other sensory neurons. This rapid, cell-selective mechanism of uptake can lead to rapid, direct interaction or binding with (1) phosphatidylinositol 4,5-bisphosphate (PIP 2) that could generate endogenous agonists of aminoglycoside permissive channels (2) mitochondria leading to generation of reactive oxygen species; (3) ribosomes and mistranslation during protein synthesis; and (4) RNA-composed nucleoli within the nucleus of cells. Potential mechanisms by which aminoglycosides are transported across the blood-labyrinth barrier into the endocochlear fluids, clearance from cells, and synergism with loop diuretics are also discussed.

Original languageEnglish (US)
Pages (from-to)299-324
Number of pages26
JournalVolta Review
Volume105
Issue number3
StatePublished - Dec 2005

Fingerprint

Aminoglycosides
pain
cause
event
interaction
Endocytosis
Cytosol
Reactive Oxygen Species
Auditory Hair Cells
Vestibular Hair Cells
Sodium Potassium Chloride Symporter Inhibitors
Kidney
Temperature
Neuromuscular Junction
Poisons
Touch
Sensory Receptor Cells
Inner Ear
Phosphatidylinositols
Cells

ASJC Scopus subject areas

  • Cultural Studies

Cite this

Cellular uptake of aminoglycosides. / Steyger, Peter.

In: Volta Review, Vol. 105, No. 3, 12.2005, p. 299-324.

Research output: Contribution to journalArticle

Steyger, P 2005, 'Cellular uptake of aminoglycosides', Volta Review, vol. 105, no. 3, pp. 299-324.
Steyger, Peter. / Cellular uptake of aminoglycosides. In: Volta Review. 2005 ; Vol. 105, No. 3. pp. 299-324.
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