Proposed molecular and cellular mechanism for aminoglycoside ototoxicity

Hutchin, Tim; Cortopassi, Gino A

doi:10.1128/aac.38.11.2517

Cited by 117 publications

(64 citation statements)

References 21 publications

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“…Positively charged aminoglycoside molecules can easily adhere electrostatically on the negatively charged cellular and mitochondrial membranes, leading to an increase in membrane permeability by lipid peroxidation. Eventually, the cellular structures leak out, and more drug influx occurs through the membranes, which ultimately results in apoptosis [9] . The free radicals, which are thought to play a role in ototoxicity, are byproducts of normal metabolism; also, they may arise from endogenous or exogenous sources such as radiation, drugs, or harmful chemicals.…”

Section: Discussionmentioning

confidence: 99%

A Prospective Experimental Study on the Protective Effect of Resveratrol against Amikacin-Induced Ototoxicity in Rats

Avcı¹,

Erkan²,

Sönmez³

et al. 2016

Int Adv Otol

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OBJECTIVE:The purpose of this study was to evaluate the protective effect of resveratrol against amikacin-induced ototoxicity in rats by otoacoustic emission and histopathology of the cochlea. MATERIALS and METHODS:This study was conducted with 31 Sprague Dawley adult female rats that were 20-21 weeks old and 190-245 g in weight. Before the drug administration, distortion product otoacoustic emission (DPOAE) tests were performed in both ears of each rat. The rats were divided into four groups. Group 1 (n=7) received ethanol 1cc 4%, Group 2 (n=8) received 600 mg/kg amikacin, Group 3 (n=8) received 10 mg/kg resveratrol and 600 mg/kg amikacin, and Group 4 (n=8) received 1cc resveratrol at 10 mg/kg. The drugs were administered once a day for 21 consecutive days. Control DPOAE tests were performed at the 7 th , 14 th , and 21 st days after the administration of drugs. At the end of the study, the rats were sacrificed and their cochleae were dissected. The cochleae were evaluated for histopathologic changes. RESULTS:There was no statistically significant difference in the DPOAE measurements before the procedure between groups. The DPOAE measurements significantly decreased after the procedure in the amikacin group. There was no statistically significant difference in DPOAE measurements after the procedure in the amikacin + resveratrol, resveratrol, and ethanol groups. The histopathologic findings supported these results. CONCLUSION:We found that if resveratrol is administered with amikacin, the severity of amikacin-induced hearing loss is decreased. These findings suggest that resveratrol, a strong antioxidant, has a protective effect in amikacin ototoxicity.

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Section: Discussionmentioning

confidence: 99%

A Prospective Experimental Study on the Protective Effect of Resveratrol against Amikacin-Induced Ototoxicity in Rats

Avcı¹,

Erkan²,

Sönmez³

et al. 2016

Int Adv Otol

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“…Floquet et al [24] described that nucleotides at position -1, -5, +4, and +8 around the premature stop codon are important to determine PTC readthrough efficiency upon gentamicin treatment. However, the strong side effects of gentamicin, the most commonly used aminoglycoside antibiotic, precludes its utilization as a potential therapeutic agent for these diseases because long-term treatment is required [25,26].…”

Section: Introductionmentioning

confidence: 99%

Effect of Readthrough Treatment in Fibroblasts of Patients Affected by Lysosomal Diseases Caused by Premature Termination Codons

et al. 2015

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Aminoglycoside antibiotics, such as gentamicin, may induce premature termination codon (PTC) readthrough and elude the nonsense-mediated mRNA decay mechanism. Because PTCs are frequently involved in lysosomal diseases, readthrough compounds may be useful as potential therapeutic agents. The aim of our study was to identify patients responsive to gentamicin treatment in order to be used as positive controls to further screen for other PTC readthrough compounds. With this aim, fibroblasts from 11 patients affected by 6 different lysosomal diseases carrying PTCs were treated with gentamicin. Treatment response was evaluated by measuring enzymatic activity, abnormal metabolite accumulation, mRNA expression, protein localization, and cell viability. The potential effect of readthrough was also analyzed by in silico predictions. Results showed that fibroblasts from 5/11 patients exhibited an up to 3-fold increase of enzymatic activity after gentamicin treatment. Accordingly, cell lines tested showed enhanced well-localized protein and/or increased mRNA expression levels and/or reduced metabolite accumulation. Interestingly, these cell lines also showed increased enzymatic activity after PTC124 treatment, which is a PTC readthroughpromoting compound. In conclusion, our results provide a proof-of-concept that PTCs can be effectively suppressed by readthrough drugs, with different efficiencies depending on the genetic context. The screening of new compounds with readthrough activity is a strategy that can be used to develop efficient therapies for diseases caused by PTC mutations.

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“…Genetic analyses of individuals hypersensitive to aminoglycosides have identified mutations in mitochondrial rRNA. Transition mutations in the mitochondrial small ribosomal RNA gene, namely A1555G and, less frequently C1494T, have been identified as primary genetic traits in aminoglycoside-induced deafness (4,6,9). A1555G and C1494T both map to the aminoacyl-tRNA acceptor site (A site) of the small ribosomal subunit.…”

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confidence: 99%

Genetic analysis of interactions with eukaryotic rRNA identify the mitoribosome as target in aminoglycoside ototoxicity

Hobbie

Subramanian

Kalapala

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

168

180

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Aminoglycoside ototoxicity has been related to a surprisingly large number of cellular structures and metabolic pathways. The finding that patients with mutations in mitochondrial rRNA are hypersusceptible to aminoglycoside-induced hearing loss has indicated a possible role for mitochondrial protein synthesis. To study the molecular interaction of aminoglycosides with eukaryotic ribosomes, we made use of the observation that the drug binding site is a distinct domain defined by the small subunit rRNA, and investigated drug susceptibility of bacterial hybrid ribosomes carrying various alleles of the eukaryotic decoding site. Compared to hybrid ribosomes with the A site of human cytosolic ribosomes, susceptibility of mitochondrial hybrid ribosomes to various aminoglycosides correlated with the relative cochleotoxicity of these drugs. Sequence alterations that correspond to the mitochondrial deafness mutations A1555G and C1494T increased drug-binding and rendered the ribosomal decoding site hypersusceptible to aminoglycoside-induced mistranslation and inhibition of protein synthesis. Our results provide experimental support for aminoglycoside-induced dysfunction of the mitochondrial ribosome. We propose a pathogenic mechanism in which interference of aminoglycosides with mitochondrial protein synthesis exacerbates the drugs' cochlear toxicity, playing a key role in sporadic dosedependent and genetically inherited, aminoglycoside-induced deafness.decoding ͉ mitochondria ͉ ribosomes ͉ toxicity ͉ translation

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Proposed molecular and cellular mechanism for aminoglycoside ototoxicity

Cited by 117 publications

References 21 publications

A Prospective Experimental Study on the Protective Effect of Resveratrol against Amikacin-Induced Ototoxicity in Rats

A Prospective Experimental Study on the Protective Effect of Resveratrol against Amikacin-Induced Ototoxicity in Rats

Effect of Readthrough Treatment in Fibroblasts of Patients Affected by Lysosomal Diseases Caused by Premature Termination Codons

Genetic analysis of interactions with eukaryotic rRNA identify the mitoribosome as target in aminoglycoside ototoxicity

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