Intracellular mechanisms of aminoglycoside-induced cytotoxicity

Oregon Hearing Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
Integrative Biology (Impact Factor: 3.76). 07/2011; 3(9):879-86. DOI: 10.1039/c1ib00034a
Source: PubMed


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.

Download full-text


Available from: Peter S Steyger
    • "The caspase enzyme system (caspase 3, 8 and 9) is activated through free oxygen radicals, the mitochondrial membrane becomes damaged and the cell goes into apoptosis, resulting in cell death. Eventually, aminoglycoside group antibiotics may be suggested as causing ototoxicity through free radicals [27,28], and this study also supports the finding that this was the active pathway of the gentamicin toxicity, since strong caspase-3 and caspase-9 expression was observed in spiral limbus and in the inner and outer hair cells in the group receiving gentamicin plus ethanol. Oxidative stress is balanced by the antioxidants that are present in physiological circumstances. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: The aim of this study is to evaluate the protective role of quercetin in gentamicin-induced ototoxicity through an auditory brainstem response (ABR) test and a histopathological evaluation of the cochlea. Methods: In this study, 48 female adult Sprague-Dawley rats aged 20-22 weeks and weighing 200-250g were used. An ABR test was carried out on all rats prior to drug administration, after which, the rats were divided into four groups of 12 animals each. Drug administration was gentamicin 120mg/kg plus ethanol in group one; gentamicin 120mg/kg plus quercetin 15mg/kg in group two; quercetin 15mg/kg in group three; and ethanol in group four. The drugs were administered intraperitoneally once a day for two weeks, and the ABR test was repeated after drug administration. Subsequently, the rats were sacrificed and their cochleae were dissected and examined histopathologically. Results: There was no significant difference between the pre-treatment ABR measurement values of the groups. However, a significant increase was detected in the ABR values in the group of rats that were administered gentamicin plus ethanol, while no statistically significant increase was found in the ABR values in the groups administered with gentamicin plus quercetin; quercetin alone; and ethanol alone. The number of TUNEL positive cells in the inner and outer hair cells in the Corti organ was found to be fewer, and Caspase 3 and 9 expressions were found to be weaker in the group receiving gentamicin plus quercetin than in the group receiving gentamicin plus ethanol. Conclusions: Auditory function was detected to be significantly protected and apoptotic cells were found to be decreased when quercetin was administered together with gentamicin. From these results it was concluded that quercetin, a powerful antioxidant, attenuates ABR thresholds and histopathological lesions in the cochlea in gentamicin-induced ototoxicity in rats.
    No preview · Article · Sep 2015 · International journal of pediatric otorhinolaryngology
  • Source
    • "The mechanism of gentamicin-induced cytotoxicity is incompletely understood. Gentamicin can induce cell death mechanisms via mitochondrial damage and caspase activation [7]–[9], as well as the generation of toxic levels of reactive oxygen species [10], [11]. Since it is difficult to inhibit the wide variety of cell death mechanisms that may be induced by gentamicin, an alternative strategy to prevent gentamicin-induced cytotoxicity is to block drug entry into cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aminoglycoside antibiotics, like gentamicin, continue to be clinically essential worldwide to treat life-threatening bacterial infections. Yet, the ototoxic and nephrotoxic side-effects of these drugs remain serious complications. A major site of gentamicin uptake and toxicity resides within kidney proximal tubules that also heavily express electrogenic sodium-glucose transporter-2 (SGLT2; SLC5A2) in vivo. We hypothesized that SGLT2 traffics gentamicin, and promotes cellular toxicity. We confirmed in vitro expression of SGLT2 in proximal tubule-derived KPT2 cells, and absence in distal tubule-derived KDT3 cells. D-glucose competitively decreased the uptake of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG), a fluorescent analog of glucose, and fluorescently-tagged gentamicin (GTTR) by KPT2 cells. Phlorizin, an SGLT2 antagonist, strongly inhibited uptake of 2-NBDG and GTTR by KPT2 cells in a dose- and time-dependent manner. GTTR uptake was elevated in KDT3 cells transfected with SGLT2 (compared to controls); and this enhanced uptake was attenuated by phlorizin. Knock-down of SGLT2 expression by siRNA reduced gentamicin-induced cytotoxicity. In vivo, SGLT2 was robustly expressed in kidney proximal tubule cells of heterozygous, but not null, mice. Phlorizin decreased GTTR uptake by kidney proximal tubule cells in Sglt2+/- mice, but not in Sglt2-/- mice. However, serum GTTR levels were elevated in Sglt2-/- mice compared to Sglt2+/- mice, and in phlorizin-treated Sglt2+/- mice compared to vehicle-treated Sglt2+/- mice. Loss of SGLT2 function by antagonism or by gene deletion did not affect gentamicin cochlear loading or auditory function. Phlorizin did not protect wild-type mice from kanamycin-induced ototoxicity. We conclude that SGLT2 can traffic gentamicin and contribute to gentamicin-induced cytotoxicity.
    Full-text · Article · Sep 2014 · PLoS ONE
  • Source
    • "A first question to be discussed concerns the distribution of gentamycin toxicity in the basal-middle cochlear turns and in the OHC inner row and IHCs. The cochlea OHCs are substantially more vulnerable to insult than IHCs, whether the insult is from aminoglycoside ototoxicity 16, excessive noise 17 or presbycusis 18. Similarly, basal turn OHCs are more vulnerable than more apically located OHCs to the "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aminoglycosides, such as gentamycin, are well known ototoxic agents. Toxicity occurs via an activation process involving the formation of an iron-gentamycin complex with free radical production. Antioxidants like Q-ter (a soluble formulation of coenzyme Q(10), CoQ(10)), can limit or prevent cellular ototoxic damage. The present study was designed to investigate the possible protective effects of Q-ter on gentamycin ototoxicity in albino guinea pigs (250-300 g). Animals were divided into five experimental groups: I, a sham control group given an intra-peritoneal (I.P.) injection of 0.5 ml saline (SHAM); II, gentamycin group (GM), treated with an injection of gentamycin (100 mg/ kg); III, gentamycin + Q-ter group (GM+Q-ter), treated with gentamycin (same dose as group II) and an I.P. injection of coenzyme Q(10) terclatrate (Q-ter) at 100 mg/kg body weight; IV, injected with gentamycin (100 mg/kg) plus saline; V, treated with Q-ter alone (100 mg/ kg). All animals were treated for 14 consecutive days. Auditory function was evaluated by recording auditory brainstem responses (ABR) at 15 and 30 days from the beginning of treatment. Morphological changes were analyzed by rhodamine-phalloidine staining. Gentamycin-induced progressive high-frequency hearing loss of 45-55 dB SPL. Q-ter therapy slowed and attenuated the progression of hearing loss, yielding a threshold shift of 20 dB. The significant loss of outer hair cells (OHCs) in the cochlear medio-basal turn in gentamycin-treated animals was not observed in the cochleae of animals protected with Q-ter. This study supports the hypothesis that Q-ter interferes with gentamycin-induced free radical formation, and suggests that it may be useful in protecting OHC function from aminoglycoside ototoxicity, thus reducing hearing loss.
    Full-text · Article · Apr 2012 · Acta otorhinolaryngologica Italica: organo ufficiale della Società italiana di otorinolaringologia e chirurgia cervico-facciale
Show more