title: Intracellular mechanisms of aminoglycoside-induced cytotoxicity.
abstract: Since introduction into clinical practice over 60 years ago, aminoglycoside antibiotics remain important drugs in the treatment of bacterial infections, cystic fibrosis and tuberculosis. However, the ototoxic and nephrotoxic properties of these drugs are still a major clinical problem. Recent advances in molecular biology and biochemistry have begun to uncover the intracellular actions of aminoglycosides that lead to cytotoxicity. In this review, we discuss intracellular binding targets of aminoglycosides, highlighting specific aminoglycoside-binding proteins (HSP73, calreticulin and CLIMP-63) and their potential for triggering caspases and Bcl-2 signalling cascades that are involved in aminoglycoside-induced cytotoxicity. We also discuss potential strategies to reduce aminoglycoside cytotoxicity, which are necessary for greater bactericidal efficacy during aminoglycoside pharmacotherapy.
authors.affiliation: Oregon Hearing Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. karasawa@ohsu.edu
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Karasawa
authors.forename: Peter S
authors.initials: PS
authors.lastname: Steyger
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D001424:Bacterial Infections / Q000188:drug therapy; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D006198:Hair Cells, Auditory / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000378:metabolism; D007668:Kidney / Q000187:drug effects; D008954:Models, Biological; D010716:Phosphatidylinositols / Q000378:metabolism; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D010716:Phosphatidylinositols; D019253:Proto-Oncogene Proteins c-bcl-2; D012313:RNA; D007501:Iron; D020169:Caspases