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Antimicrob Agents Chemother


Antibiotics and the Mitochondria 

Marlene E. Kunold: 

Antibiotics, Marching on the Path of human Extinction  

http://www.lyme-borreliose-hamburg.de/press/MEK-Antibiotics.pdf 
 

Antibacterial drugs and their interference with the biogenesis of mitochondria in animal and human cells

http://www.ummafrapp.de/skandal/felix/antibiotics/antibacterial_drugs.pdf 

The biogenesis of mitochondria, VI. Biochemical basis of the resistance of

Saccharomyces cerevisiae toward antibiotics which specifically inhibit

mitochondrial protein synthesis.

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=224865&blobtype=pdf 

Biogenesis of mitochondria. XI. A comparison of the effects of growth-limiting oxygen

tension, intercalating agents, and antibiotics on the obligate aerobe Candida

parapsilosis.

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2107676&blobtype=pdf 

Biogenesis of Mitochondria: Analysis of Deletion of Mitochondrial Antibiotic Resistance Markers in Petite Mutants of Saccharomyces cerevisiae.

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=235632&blobtype=pdf 

Influence on Mitochondria and Cytotoxicity of Different Antibiotics Administered in High Concentrations on Primary Human Osteoblasts and Cell Lines

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1797653&blobtype=pdf 

Structural basis for selectivity and toxicity of ribosomal antibiotics

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1083859&blobtype=pdf 

Familial streptomycin ototoxicity in a South African Family: A mitochondrial disorder

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1051117&blobtype=pdf 

The Renal Mitochondrial Toxicity of Beta-Lactam Antibiotics: In Vitro Effects of

Cephaloglycin and Imipenem

http://jasn.asnjournals.org/cgi/reprint/1/5/815 

Cephaloridine Induces Translocation of Protein Kinase C δInto Mitochondria and Enhances Mitochondrial Generation of Free Radicals in the Kidney Cortex of Rats Causing Renal Dysfunction

http://www.jstage.jst.go.jp/article/jphs/98/1/49/_pdf 

Mitochondrial DNA Deletions and Chloramphenicol Treatment Stimulate

the Autophagic Transcript ATG12

http://www.landesbioscience.com/journals/autophagy/article/prigioneAUTO3-4.pdf 

Chloramphenicol-induced Mitochondrial Stress Increases p21 Expression and Prevents Cell Apoptosis through a p21-dependent Pathway*

http://www.jbc.org/cgi/reprint/280/28/26193 

Inhibition of mammalian mitochondrial protein synthesis by Oxazolidinones

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1479116&blobtype=pdf 

Ciprofloxacin does not inhibit mitochondrial functions but other antibiotics do

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=171543&blobtype=pdf 

In vitro and in vivo immunomodulatory effects of anti-Pneumocystis carinii drugs.

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=163313&blobtype=pdf 

The Sensitivity of Rat Liver and Yeast Mitochondrial Ribosomes to inhibitors of protein synthesis

http://www.jbc.org/cgi/reprint/249/21/6806 

Antimicrob Agents Chemother. 2006 Jun;50(6):2042-9.

Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones.

McKee EE, Ferguson M, Bentley AT, Marks TA.

Source

Indiana University School of Medicine--South Bend, IN 46617, USA. McKee.6@nd.edu

Abstract

The effects of a variety of oxazolidinones, with different antibacterial potencies, including linezolid, on mitochondrial protein synthesis were determined in intact mitochondria isolated from rat heart and liver and rabbit heart and bone marrow. The results demonstrate that a general feature of the oxazolidinone class of antibiotics is the inhibition of mammalian mitochondrial protein synthesis. Inhibition was similar in mitochondria from all tissues studied. Further, oxazolidinones that were very potent as antibiotics were uniformly potent in inhibiting mitochondrial protein synthesis. These results were compared to the inhibitory profiles of other antibiotics that function by inhibiting bacterial protein synthesis. Of these, chloramphenicol and tetracycline were significant inhibitors of mammalian mitochondrial protein synthesis while the macrolides, lincosamides, and aminoglycosides were not. Development of future antibiotics from the oxazolidinone class will have to evaluate potential mitochondrial toxicity.

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Toxicol Sci. 2010 Jul;116(1):140-50. Epub 2010 Mar 25.

Chloramphenicol causes mitochondrial stress, decreases ATP biosynthesis, induces matrix metalloproteinase-13 expression, and solid-tumor cell invasion.

Li CH, Cheng YW, Liao PL, Yang YT, Kang JJ.

Source

Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.

Abstract

Overuse and abuse of antibiotics can increase the risk of cancer. Chloramphenicol can inhibit both bacterial and mitochondrial protein synthesis, causing mitochondrial stress and decreased ATP biosynthesis. Chloramphenicol can accelerate cancer progression; however, the underlying mechanisms of chloramphenicol in carcinogenesis and cancer progression are still unclear. We found that chloramphenicol can induce matrix metalloproteinase (MMP)-13 expression and increase MMP-13 protein in conditioned medium, resulting in an increase in cancer cell invasion. Chloramphenicol also activated c-Jun N-terminal kinases (JNK) and phosphatidylinositol 3-kinase (PI-3K)/Akt signaling, leading to c-Jun protein phosphorylation. The activated c-Jun protein has been proven to activate binding to the MMP-13 promoter and also upregulate the amount of MMP-13. Both the SP 600125 (JNK inhibitor) and LY 294002 (PI-3K/Akt inhibitor) can inhibit chloramphenicol-induced c-Jun phosphorylation, MMP-13 expression, and cell invasion. Overexpression of the dominant-negative JNK and PI-3K p85 subunit also negate chloramphenicol-induced responses. Other antibiotics that cause mitochondrial stress and a decrease in ATP biosynthesis also induce MMP-13 expression. These findings suggest that chloramphenicol-induced PI-3K/Akt, JNK phosphorylation, and activator protein 1 activation might function as a novel mitochondrial stress signal that result in an increase of MMP-13 expression and MMP-13-associated cancer cell invasion. The findings of this study confirms that chloramphenicol, and other 70S ribosomal inhibitors, should be administered with caution, especially during cancer therapy.

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Antimicrob Agents Chemother. 1998 Aug;42(8):1923-30.

Ciprofloxacin induces an immunomodulatory stress response in human T lymphocytes.

Riesbeck K, Forsgren A, Henriksson A, Bredberg A.

Source

Department of Medical Microbiology, Lund University, Malm� University Hospital, S-205 02 Malm�, Sweden. riesbeck@mikrobiol.mas.lu.se

Abstract

Exposure of cells to adverse environmental conditions invokes a genetically programmed series of events resulting in the induction of specific genes. The fluoroquinolone antibiotic ciprofloxacin has recently been reported to upregulate interleukin-2 (IL-2) gene induction. In the present investigation, the effect of ciprofloxacin at supratherapeutic concentrations on immediate-early (<2 h) gene expression in primary human peripheral blood lymphocytes was studied with Northern blots. In addition, transcriptional activity of IL-2 and metallothionein enhancer and promoter regions and transcription factors AP-1, NF-kappaB, and NF-AT were analyzed by chloramphenicol acetyltransferase (CAT) and electrophoretic mobility shift assays, respectively. The concentration of c-fos, c-jun, c-myc, junB, and fra-1 mRNAs was increased in activated peripheral blood lymphocytes incubated with ciprofloxacin compared to that in untreated controls. Ciprofloxacin increased CAT activity in stimulated lymphocytes transfected with plasmids containing either the IL-2 or metallothionein enhancer. Furthermore, among the transcription factors tested, AP-1 activity was increased in stimulated purified T helper lymphocytes incubated with ciprofloxacin compared to drug-free controls. Taken together, ciprofloxacin increased the levels of immediate-early transcripts, enhanced IL-2 and metallothionein promoter induction, and upregulated AP-1 concentrations in primary lymphocytes, reflecting a program commonly observed in mammalian stress responses.

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Antimicrob Agents Chemother. 1990 Jan;34(1):167-9.

Ciprofloxacin does not inhibit mitochondrial functions but other antibiotics do.

Riesbeck K, Bredberg A, Forsgren A.

Source

Department of Medical Microbiology, University of Lund, Malm� General Hospital, Sweden.

Abstract

At clinical concentrations, ciprofloxacin did not inhibit mitochondrial DNA replication, oxidative phosphorylation, protein synthesis, or mitochondrial mass (transmembrane potential). No difference in supercoiled forms of DNA was observed. The tetracyclines and chloramphenicol inhibited protein synthesis at clinically achievable concentrations, while rifampin, fusidic acid, and clindamycin did not.

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Chem Biol Interact. 2008 Jun 17;173(3):187-94. Epub 2008 Mar 21.

Interaction of beta-lactam antibiotics with the mitochondrial carnitine/acylcarnitine transporter.

Pochini L, Galluccio M, Scumaci D, Giangregorio N, Tonazzi A, Palmieri F, Indiveri C.

Source

Department of Cell Biology, University of Calabria, Via P.Bucci 4c, 87036 Arcavacata di Rende, Italy.

Abstract

The interaction of beta-lactams with the purified mitochondrial carnitine/acylcarnitine transporter reconstituted in liposomes has been studied. Cefonicid, cefazolin, cephalothin, ampicillin, piperacillin externally added to the proteoliposomes, inhibited the carnitine/carnitine antiport catalysed by the reconstituted transporter. The most effective inhibitors were cefonicid and ampicillin with IC50 of 6.8 and 7.6mM, respectively. The other inhibitors exhibited IC50 values above 36 mM. Kinetic analysis performed with cefonicid and ampicillin revealed that the inhibition is completely competitive, i.e., the inhibitors interact with the substrate binding site. The Ki of the transporter is 4.9 mM for cefonicid and 9.9 mM for ampicillin. Cefonicid inhibited the transporter also on its internal side. The IC50 was 12.9 mM indicating that the inhibition was less pronounced than on the external side. Ampicillin and the other inhibitors were much less effective on the internal side. The beta-lactams were not transported by the carnitine/acylcarnitine transporter. Cephalosporins, and at much lower extent penicillins, caused irreversible inhibition of the transporter after prolonged time of incubation. The most effective among the tested antibiotics was cefonicid with IC50 of 0.12 mM after 60 h of incubation. The possible in vivo implications of the interaction of the beta-lactam antibiotics with the transporter are discussed.

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Antimicrob Agents Chemother. 2005 Sep;49(9):3896-902.

Oxazolidinones inhibit cellular proliferation via inhibition of mitochondrial protein synthesis.

Nagiec EE, Wu L, Swaney SM, Chosay JG, Ross DE, Brieland JK, Leach KL.

Source

Department of Antibacterial Pharmacology, Pfizer, Ann Arbor, MI 48105, USA.

Abstract

The oxazolidinones are a relatively new structural class of antibacterial agents that act by inhibiting bacterial protein synthesis. The oxazolidinones inhibit mitochondrial protein synthesis, as shown by [35S]methionine incorporation into intact rat heart mitochondria. Treatment of K562 human erythroleukemia cells with the oxazolidinone eperezolid resulted in a time- and concentration-dependent inhibition of cell proliferation. The cells remained viable, but an increase in doubling time was observed with eperezolid treatment. Inhibition was reversible, since washing and refeeding of cells in the absence of compound resulted in a resumption of growth. The growth-inhibitory effect of the oxazolidinones did not appear to be cell type specific, and inhibition of CHO and HEK cells also was demonstrated. Treatment of cells resulted in a decrease in mitochondrial cytochrome oxidase subunit I levels, consistent with an inhibition of mitochondrial protein synthesis. Eperezolid caused no growth inhibition of rho zero (rho0) cells, which contain no mitochondrial DNA; however, the growth of the parent 143B cells was inhibited. These results provide a direct demonstration that the inhibitory effect of eperezolid in mammalian cells is the result of mitochondrial protein synthesis inhibition.

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Antimicrob Agents Chemother. 2007 Jan;51(1):54-63. Epub 2006 Nov 6.

Influence on mitochondria and cytotoxicity of different antibiotics administered in high concentrations on primary human osteoblasts and cell lines.

Duewelhenke N, Krut O, Eysel P.

Source

Klinik und Poliklinik f�r Orthop�die, Universit�tsklinikum K�ln, Joseph-Stelzmann-Str. 24, 50931 K�ln, Germany. Nicole.Duewelhenke@uk-koeln.de

Abstract

Osteomyelitis, osteitis, spondylodiscitis, septic arthritis, and prosthetic joint infections still represent the worst complications of orthopedic surgery and traumatology. Successful treatment requires, besides surgical d�bridement, long-term systemic and high-concentration local antibiotic therapy, with possible local antibiotic concentrations of 100 microg/ml and more. In this study, we investigated the effect of 20 different antibiotics on primary human osteoblasts (PHO), the osteosarcoma cell line MG63, and the epithelial cell line HeLa. High concentrations of fluoroquinolones, macrolides, clindamycin, chloramphenicol, rifampin, tetracycline, and linezolid during 48 h of incubation inhibited proliferation and metabolic activity, whereas aminoglycosides and inhibitors of bacterial cell wall synthesis did not. Twenty percent inhibitory concentrations for proliferation of PHO were determined as 20 to 40 microg/ml for macrolides, clindamycin, and rifampin, 60 to 80 microg/ml for chloramphenicol, tetracylin, and fluoroquinolones, and 240 microg/ml for linezolid. The proliferation of the cell lines was always less inhibited. We established the measurement of extracellular lactate concentration as an indicator of glycolysis using inhibitors of the respiratory chain (antimycin A, rotenone, and sodium azide) and glycolysis (iodoacetic acid) as reference compounds, whereas inhibition of the respiratory chain increased and inhibition of glycolysis decreased lactate production. The measurement of extracellular lactate concentration revealed that fluoroquinolones, macrolides, clindamycin, rifampin, tetracycline, and especially chloramphenicol and linezolid impaired mitochondrial energetics in high concentrations. This explains partly the observed inhibition of metabolic activity and proliferation in our experiments. Because of differences in the energy metabolism, PHO provided a more sensitive model for orthopedic antibiotic usage than stable cell lines.

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Biochem Pharmacol. 2009 Mar 1;77(5):888-96. Epub 2008 Nov 12.

Inhibitory modulation of the mitochondrial permeability transition by minocycline.

Gieseler A, Schultze AT, Kupsch K, Haroon MF, Wolf G, Siemen D, Kreutzmann P.

Source

Institute of Medical Neurobiology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany.

Abstract

The semi-synthetic tetracycline derivative minocycline exerts neuroprotective properties in various animal models of neurodegenerative disorders. Although anti-inflammatory and anti-apoptotic effects are reported to contribute to the neuroprotective action, the exact molecular mechanisms underlying the beneficial properties of minocycline remain to be clarified. We analyzed the effects of minocycline in a cell culture model of neuronal damage and in single-channel measurements on isolated mitoplasts. Treatment of neuron-enriched cortical cultures with rotenone, a high affinity inhibitor of the mitochondrial complex I, resulted in a deregulation of the intracellular Ca2+-dynamics, as recorded by live cell imaging. Minocycline (100 microM) and cyclosporin A (2 microM), a known inhibitor of the mitochondrial permeability transition pore, decreased the rotenone-induced Ca2+-deregulation by 60.9% and 37.6%, respectively. Investigations of the mitochondrial permeability transition pore by patch-clamp techniques revealed for the first time a dose-dependent reduction of the open probability by minocycline (IC(50)=190 nM). Additionally, we provide evidence for the high antioxidant potential of MC in our model. In conclusion, the present data substantiate the beneficial properties of minocycline as promising neuroprotectant by its inhibitory activity on the mitochondrial permeability transition pore.

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Biochem Biophys Res Commun. 2008 Apr 11;368(3):631-6. Epub 2008 Feb 7.

A mutation in mitochondrial 12S rRNA, A827G, in Argentinean family with hearing loss after aminoglycoside treatment.

Chaig MR, Zernotti ME, Soria NW, Romero OF, Romero MF, Gerez NM.

Source

C�tedra de Bioqu�mica y Biolog�a molecular, FCM-UNC, Haya de la Torre, S/N Ciudad Universitaria, 2do, Piso, Pabell�n CP 5016, Argentina.

Abstract

Mutations in mitochondrial DNA (mtDNA) have been found to be associated with sensorineural hearing loss. We report the clinical, genetic, and molecular characterization of one Argentinean family with aminoglycoside-induced impairment in two of their members. Clinical evaluation revealed the variable phenotype of hearing impairment including audiometric configuration in these subjects. Mutational analysis of the mtDNA in these pedigrees showed the presence of homoplasmic 12S rRNA A827G mutation, which has been associated with hearing impairment. The A827G mutation is located at the A-site of the mitochondrial 12S rRNA gene which is highly conserved in mammals. It is possible that the alteration of the tertiary or quaternary structure of this rRNA by the A827G mutation may lead to mitochondrial dysfunction, thereby playing a role in the pathogenesis of hearing loss and aminoglycoside hypersensitivity. However, incomplete penetrance of hearing impairment indicates that the A827G mutation itself is not sufficient to produce clinical phenotype.

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Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20888-93. Epub 2008 Dec 22.

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

Hobbie SN, Akshay S, Kalapala SK, Bruell CM, Shcherbakov D, B�ttger EC.

Source

Institut f�r Medizinische Mikrobiologie, Universit�t Z�rich, Gloriastrasse 32, CH-8006 Zurich, Switzerland.

Abstract

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 dose-dependent and genetically inherited, aminoglycoside-induced deafness.

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J Med Genet. 1997 Nov;34(11):904-6.

Familial streptomycin ototoxicity in a South African family: a mitochondrial disorder.

Gardner JC, Goliath R, Viljoen D, Sellars S, Cortopassi G, Hutchin T, Greenberg J, Beighton P.

Source

Department of Human Genetics, University of Cape Town Medical School, Observatory, South Africa.

Abstract

The vestibular and ototoxic effects of the aminoglycoside antibiotics (streptomycin, gentamycin, kanamycin, tobramycin, neomycin) are well known; streptomycin, in particular, has been found to cause irreversible, profound, high frequency sensorineural deafness in hypersensitive persons. Aminoglycoside ototoxicity occurs both sporadically and within families and has been associated with a mitochondrial DNA (mtDNA) 1555A to G point mutation in the 12S ribosomal RNA gene. We report on the molecular analysis of a South African family with streptomycin induced sensorineural deafness in which we have found transmission of this same predisposing mutation. It is now possible to identify people who are at risk of hearing loss if treated with aminoglycosides in the future and to counsel them accordingly. In view of the fact that aminoglycoside antibiotics remain in widespread use for the treatment of infections, in particular for tuberculosis, which is currently of epidemic proportions in South Africa, this finding has important implications for the family concerned. In addition, other South African families may potentially be at risk if they carry the same mutation.

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J Biol Chem. 2005 Jul 15;280(28):26193-9. Epub 2005 May 19.

Chloramphenicol-induced mitochondrial stress increases p21 expression and prevents cell apoptosis through a p21-dependent pathway.

Li CH, Tzeng SL, Cheng YW, Kang JJ.

Source

Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.

Abstract

Pretreatment of HepG2 and H1299 cells with chloramphenicol rendered the cells resistant to mitomycin-induced apoptosis. Both mitomycin-induced caspase 3 activity and PARP activation were also inhibited. The mitochondrial DNA-encoded Cox I protein, but not nuclear-encoded proteins, was down-regulated in chloramphenicol-treated cells. Cellular levels of the p21(waf1/cip1) protein and p21(waf1/cip1) mRNA were increased through a p53-independent pathway, possibly because of the stabilization of p21(waf1/cip1) mRNA in chloramphenicol-treated cells. The p21(waf1/cip1) was redistributed from the perinuclear region to the cytoplasm and co-localized with mitochondrial marker protein. Several morphological changes and activation of the senescence-associated biomarker, SA beta-galactosidase, were observed in these cells. Both p21(waf1/cip1) antisense and small interfering RNA could restore apoptotic-associated caspase 3 activity, PARP activation, and sensitivity to mitomycin-induced apoptosis. Similar effects were seen with other antibiotics that inhibit mitochondrial translation, including minocycline, doxycycline, and clindamycin. These findings suggested that mitochondrial stress causes resistance to apoptosis through a p21-dependent pathway.

Supplemental Content

 
 

Biochem Pharmacol. 2009 Mar 1;77(5):888-96. Epub 2008 Nov 12.

Inhibitory modulation of the mitochondrial permeability transition by minocycline.

Gieseler A, Schultze AT, Kupsch K, Haroon MF, Wolf G, Siemen D, Kreutzmann P.

Source

Institute of Medical Neurobiology, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany.

Abstract

The semi-synthetic tetracycline derivative minocycline exerts neuroprotective properties in various animal models of neurodegenerative disorders. Although anti-inflammatory and anti-apoptotic effects are reported to contribute to the neuroprotective action, the exact molecular mechanisms underlying the beneficial properties of minocycline remain to be clarified. We analyzed the effects of minocycline in a cell culture model of neuronal damage and in single-channel measurements on isolated mitoplasts. Treatment of neuron-enriched cortical cultures with rotenone, a high affinity inhibitor of the mitochondrial complex I, resulted in a deregulation of the intracellular Ca2+-dynamics, as recorded by live cell imaging. Minocycline (100 microM) and cyclosporin A (2 microM), a known inhibitor of the mitochondrial permeability transition pore, decreased the rotenone-induced Ca2+-deregulation by 60.9% and 37.6%, respectively. Investigations of the mitochondrial permeability transition pore by patch-clamp techniques revealed for the first time a dose-dependent reduction of the open probability by minocycline (IC(50)=190 nM). Additionally, we provide evidence for the high antioxidant potential of MC in our model. In conclusion, the present data substantiate the beneficial properties of minocycline as promising neuroprotectant by its inhibitory activity on the mitochondrial permeability transition pore.

Supplemental Content

 

Tetracycline treatment influences mitochondrial metabolism and mtDNA density two generations after treatment in Drosophila.

     Ballard JW, Melvin RG.

    Ramaciotti Centre for Gene Function Analysis, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia. w.ballard@unsw.edu.au

    Tetracycline is commonly used to clear Wolbachia from infected insects. Studies then compare specific biochemical and/or life-history traits between infected and uninfected individuals with the same genetic background. We investigated the potential for tetracycline to influence mitochondrial efficiency and mitochondrial (mt)DNA density two generations after treatment in Drosophila simulans. We observed that antibiotic treatment resulted in a decline in inorganic phosphate incorporated into ATP per mole of oxygen consumed (ADP:O ratio). Further, tetracycline treatment caused a significant increase in mtDNA density in naturally Wolbachia-uninfected but not in naturally Wolbachia-infected lines suggesting a dosage effect. These data suggest that the current practice of comparing Wolbachia-infected and Wolbachia-uninfected insects two generations after tetracycline treatment needs to be re-evaluated. 

    Swiss Med Wkly. 2010 Sep 24;140:w13080. doi: 10.4414/smw.2010.13080.

    Liver injury caused by drugs: an update.

    Stirnimann G, Kessebohm K, Lauterburg B.

    Source

    Institut for clinical pharmacology and Visceral Research, University of Bern, Bern, Switzerland.

    Abstract

    Although severe idiosyncratic drug-induced liver injury (DILI) is a rare event, it has a large impact on the fate of affected patients and the incriminated drug. Hepatic metabolism of drugs, which occurs in the generation of chemically reactive metabolites in critical amounts, seems to underlie most instances of DILI. Genetic polymorphisms in activating and detoxifying enzymes determine, in part, the extent of cellular stress. A cascade of events, where the pathogenetic relevance of single steps is likely to vary from drug to drug, leads to the disturbance of cellular homeostasis, to mitochondrial dysfunction, to the activation of cell death promoting pathways and the release of drug-modified macromolecules and/or danger signals that initiate an innate and/or adaptive immune response. The patient's response to the initial drug-induced cellular dysfunction determines whether adaptation to the drug-induced cellular stress or DILI in one of its many forms of clinical presentation occurs. Although risk factors for developing DILI have been identified and many pathogenetic mechanisms have been elucidated in model systems, idiosyncratic drug reactions remain unpredictable.

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    Toxicol Sci. 2011 Feb;119(2):245-56. Epub 2010 Sep 9.

    An integrative overview on the mechanisms underlying the renal tubular cytotoxicity of gentamicin.

    Quiros Y, Vicente-Vicente L, Morales AI, L�pez-Novoa JM, L�pez-Hern�ndez FJ.

    Source

    Departamento de Fisiolog�a y Farmacolog�a, Universidad de Salamanca, 37007 Salamanca, Spain.

    Abstract

    Gentamicin is an aminoglycoside antibiotic widely used against infections by Gram-negative microorganisms. Nephrotoxicity is the main limitation to its therapeutic efficacy. Gentamicin nephrotoxicity occurs in 10-20% of therapeutic regimes. A central aspect of gentamicin nephrotoxicity is its tubular effect, which may range from a mere loss of the brush border in epithelial cells to an overt tubular necrosis. Tubular cytotoxicity is the consequence of many interconnected actions, triggered by drug accumulation in epithelial tubular cells. Accumulation results from the presence of the endocytic receptor complex formed by megalin and cubulin, which transports proteins and organic cations inside the cells. Gentamicin then accesses and accumulates in the endosomal compartment, the Golgi and endoplasmic reticulum (ER), causes ER stress, and unleashes the unfolded protein response. An excessive concentration of the drug over an undetermined threshold destabilizes intracellular membranes and the drug redistributes through the cytosol. It then acts on mitochondria to unleash the intrinsic pathway of apoptosis. In addition, lysosomal cathepsins lose confinement and, depending on their new cytosolic concentration, they contribute to the activation of apoptosis or produce a massive proteolysis. However, other effects of gentamicin have also been linked to cell death, such as phospholipidosis, oxidative stress, extracellular calcium-sensing receptor stimulation, and energetic catastrophe. Besides, indirect effects of gentamicin, such as reduced renal blood flow and inflammation, may also contribute or amplify its cytotoxicity. The purpose of this review was to critically integrate all these effects and discuss their relative contribution to tubular cell death.

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    Chem Biol Interact. 2010 Oct 6;188(1):204-13. Epub 2010 Jul 23.

    Trovafloxacin, a fluoroquinolone antibiotic with hepatotoxic potential, causes mitochondrial peroxynitrite stress in a mouse model of underlying mitochondrial dysfunction.

    Hsiao CJ, Younis H, Boelsterli UA.

    Source

    University of Connecticut, School of Pharmacy, Department of Pharmaceutical Sciences, Storrs, CT 06269-3092, USA.

    Abstract

    Trovafloxacin (TVX) is a fluoroquinolone antibiotic whose therapeutic use was severely restricted due to an unacceptable risk of idiosyncratic liver injury. Oxidative stress and mitochondrial injury have been implicated in fluoroquinolone toxicity, but the mechanisms underlying liver injury are poorly understood. Because TVX-induced hepatotoxicity cannot be modeled in normal healthy rodents, we asked whether an underlying genetic defect (heterozygous deficiency in mitochondrial superoxide dismutase, Sod2) might aggravate TVX-induced mitochondrial adverse effects. Wild-type and Sod2(+/-) mice were treated with vehicle or alatrofloxacin (the prodrug of TVX, 33mg/kg/day, ip) for 28 days. We found that hepatic protein carbonyls were increased by 2.5-fold and hepatic mitochondrial aconitase activity was decreased by 20% in mutant, but not wild-type mice. Because aconitase is a major target of peroxynitrite, we determined the extent of nitrotyrosine residues in hepatic mitochondrial proteins. Trovafloxacin significantly increased nitrotyrosine in Sod2(+/-) mice only. Using the NO-selective probe DAF-2, we found that TVX increased the production of mitochondrial NO in immortalized human hepatocytes. Similarly, mitochondrial Ca(2+) was increased by TVX, suggesting Ca(2+)-dependent activation of mitochondrial NOS activity. Furthermore, the transcript levels of the mtDNA-encoded gene Cox2/mtCo2 were decreased in Sod2(+/-) mice only, while the expression of nDNA-encoded mitochondrial genes was not significantly altered in both genotypes, suggesting selective effects on mtDNA expression. The amount of mtDNA (copy number) was, however, unchanged. These data indicate that TVX enhances hepatic mitochondrial peroxynitrite stress in mice with underlying increased basal levels of superoxide, leading to the disruption of critical mitochondrial enzymes and gene regulation.

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    Toxicol In Vitro. 2010 Jun;24(4):1111-8. Epub 2010 Mar 21.

    The effects of antimycin A on endothelial cells in cell death, reactive oxygen species and GSH levels.

    You BR, Park WH.

    Source

    Department of Physiology, Medical School, Research Institute of Clinical Medicine, Chonbuk National University, JeonJu 561-180, Republic of Korea.

    Abstract

    Antimycin A (AMA) inhibits mitochondrial electron transport chain between cytochrome b and c. Here, we evaluated the effects of AMA on the growth and death of endothelial cells (ECs) in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. AMA inhibited the growth of calf pulmonary artery endothelial cells (CPAEC) and human umbilical vein endothelial cells (HUVEC). AMA also induced apoptosis in both ECs which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). HUVEC were more sensitive to AMA than CPAEC. AMA increased ROS level in CPAEC but decreased the levels in HUVEC. Z-VAD (pan-caspase inhibitor) mildly prevented apoptosis in AMA-treated ECs without the significant changes of ROS. N-acetyl-cysteine (NAC; a well-known antioxidant) decreased ROS levels in AMA-treated ECs. NAC reduced CPAEC death by AMA but enhanced HUVEC death by it. Furthermore, AMA increased GSH depleted cell numbers in ECs. Buthionine sulfoximine (BSO; an inhibitor of GSH synthesis), showing a pro-apoptotic effect on AMA-treated HUVEC, significantly increased GSH depleted cell number but it did not affect cell death and GSH depletion in AMA-treated CPAEC. In conclusion, AMA inhibited the growth of ECs via caspase-dependent apoptosis. ROS level change by AMA was partially related to CPAEC death, but did not affect HUVEC death. The change of GSH contents by AMA influenced the death of ECs.

    Copyright 2010 Elsevier Ltd. All rights reserved.

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    Mitochondrion. 2010 Mar;10(2):115-24. Epub 2009 Nov 10.

    Ethambutol-induced optic neuropathy linked to OPA1 mutation and mitochondrial toxicity.

    Guillet V, Chevrollier A, Cassereau J, Letournel F, Gueguen N, Richard L, Desquiret V, Verny C, Procaccio V, Amati-Bonneau P, Reynier P, Bonneau D.

    Source

    INSERM, U694, Angers, F-49000, France.

    Abstract

    Ethambutol (EMB), widely used in the treatment of tuberculosis, has been reported to cause Leber's hereditary optic neuropathy in patients carrying mitochondrial DNA mutations. We study the effect of EMB on mitochondrial metabolism in fibroblasts from controls and from a man carrying an OPA1 mutation, in whom the drug induced the development of autosomal dominant optic atrophy (ADOA). EMB produced a mitochondrial coupling defect together with a 25% reduction in complex IV activity. EMB induced the formation of vacuoles associated with decreased mitochondrial membrane potential and increased fragmentation of the mitochondrial network. Mitochondrial genetic variations may therefore be predisposing factors in EMB-induced ocular injury.

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    Nephrol Dial Transplant. 2010 Jan;25(1):69-76. Epub 2009 Sep 8.

    Increased urinary losses of carnitine and decreased intramitochondrial coenzyme A in gentamicin-induced acute renal failure in rats.

    Al-Shabanah OA, Aleisa AM, Al-Yahya AA, Al-Rejaie SS, Bakheet SA, Fatani AG, Sayed-Ahmed MM.

    Source

    Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Kingdom of Saudi Arabia.

    Abstract

    BACKGROUND:

    This study examined whether carnitine deficiency is a risk factor and should be viewed as a mechanism during the development of gentamicin (GM)-induced ARF as well as exploring if carnitine supplementation could offer protection against this toxicity.

    METHODS:

    Adult male Wistar albino rats were assigned to one of six treatment groups: group 1 (control) rats were given daily intraperitoneal (I.P.) injections of normal saline for 8 consecutive days; groups 2, 3 and 4 rats were given GM (80 mg/kg/day, I.P.), l-carnitine (200 mg/kg/day, I.P.) and d-carnitine (250 mg/kg/day, I.P.), respectively, for 8 consecutive days. Rats of group 5 (GM plus d-carnitine) received a daily I.P. injection of d-carnitine (250 mg/kg/day) 1 h before GM (80 mg/kg/day) for 8 consecutive days. Rats of group 6 (GM plus l-carnitine) received a daily I.P. injection of l-carnitine (200 mg/kg/day) 1 h before GM (80 mg/kg/day) for 8 consecutive days.

    RESULTS:

    GM significantly increased serum creatinine, blood urea nitrogen (BUN), urinary carnitine excretion, intramitochondrial acetyl-CoA and total nitrate/nitrite (NOx) and thiobarbituric acid reactive substances (TBARS) in kidney tissues and significantly decreased total carnitine, intramitochondrial CoA-SH, ATP, ATP/ADP and reduced glutathione (GSH) in kidney tissues. In carnitine-depleted rats, GM caused a progressive increase in serum creatinine, BUN and urinary carnitine excretion and a progressive decrease in total carnitine, intamitochondrial CoA-SH and ATP. Interestingly, l-carnitine supplementation resulted in a complete reversal of the increase in serum creatinine, BUN, urinary carnitine excretion and the decrease in total carnitine, intramitochondrial CoA-SH and ATP, induced by GM, to the control values. Moreover, the histopathological examination of kidney tissues confirmed the biochemical data, where l-carnitine prevents and d-carnitine aggravates GM-induced ARF.

    CONCLUSIONS:

    (i) GM-induced nephrotoxicity leads to increased urinary losses of carnitine; (ii) carnitine deficiency is a risk factor and should be viewed as a mechanism during the development of GM-induced ARF; and (iii) carnitine supplementation ameliorates the severity of GM-induced kidney dysfunction by increasing the intramitochondrial CoA-SH/acetyl-CoA ratio and ATP production.

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    J Pharmacol Sci. 2009 May;110(1):69-77. Epub 2009 Apr 29.

    Rokitamycin induces a mitochondrial defect and caspase-dependent apoptosis in human T-cell leukemia Jurkat cells.

    Fukui M, Nagahara Y, Nishio Y, Honjoh T, Shinomiya T.

    Source

    Department of Pharmacology, University of Kansas Medical Center, Kansas City, KS 66160, USA.

    Abstract

    Macrolides are a well-known family of oral antibiotics whose antibacterial spectrum of activity covers most relevant bacterial species responsible for respiratory infectious disease. In recent years, it has been reported that macrolides have not only bactericidal activity but also direct immunomodulating activity in mammals. In this study, we observed new physiological activity of macrolides and examined whether various macrolides induce apoptosis in human leukemia cell lines. We investigated the effects of 13 different macrolides on the viability of Jurkat and HL-60 cells. Among all the macrolides used in this study, rokitamycin, a semisynthetic macrolide with a 16-member ring, effectively induced cell death. Rokitamycin induced DNA fragmentation and caspase activation, resembling the progression of apoptosis. Moreover, rokitamycin reduced the mitochondrial transmembrane potential and released cytochrome c from mitochondria to the cytosol, suggesting that mitochondrial perturbation is involved in rokitamycin-induced apoptosis. These results suggest that rokitamycin possesses not only bactericidal activity but also pro-apoptotic activity in human leukemia cells.

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    Noise Health. 2009 Jan-Mar;11(42):26-32.

    Synergistic ototoxicity due to noise exposure and aminoglycoside antibiotics.

    Li H, Steyger PS.

    Source

    Oregon Hearing Research Center, Oregon Health and Science University, Portland, Oregon, USA.

    Abstract

    Acoustic exposure to high intensity and/or prolonged noise causes temporary or permanent threshold shifts in auditory perception, reflected by reversible or irreversible damage in the cochlea. Aminoglycoside antibiotics, used for treating or preventing life-threatening bacterial infections, also induce cytotoxicity in the cochlea. Combined noise and aminoglycoside exposure, particularly in neonatal intensive care units, can lead to auditory threshold shifts greater than simple summation of the two insults. The synergistic toxicity of acoustic exposure and aminoglycoside antibiotics is not limited to simultaneous exposures. Prior acoustic insult which does not result in permanent threshold shifts potentiates aminoglycoside ototoxicity. In addition, exposure to subdamaging doses of aminoglycosides aggravates noise-induced cochlear damage. The mechanisms by which aminoglycosides cause auditory dysfunction are still being unraveled, but likely include the following: 1) penetration into the endolymphatic fluid of the scala media, 2) permeation of nonselective cation channels on the apical surface of hair cells, and 3) generation of toxic reactive oxygen species and interference with other cellular pathways. Here we discuss the effect of combined noise and aminoglycoside exposure to identify pivotal synergistic events that can potentiate ototoxicity, in addition to a current understanding of aminoglycoside trafficking within the cochlea. Preventing the ototoxic synergy of noise and aminoglycosides is best achieved by using non-ototoxic bactericidal drugs, and by attenuating perceived noise intensity when life-saving aminoglycoside therapy is required.

    Supplemental Content

     
     

    Toxicol Sci. 2009 Jan;107(1):258-69. Epub 2008 Oct 16.

    Gene expression analysis reveals new possible mechanisms of vancomycin-induced nephrotoxicity and identifies gene markers candidates.

    Dieterich C, Puey A, Lin S, Swezey R, Furimsky A, Fairchild D, Mirsalis JC, Ng HH.

    Source

    Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, California 94025-3493, USA.

    Erratum in

    • Toxicol Sci. 2009 Mar;108(1):222. Lyn, Sylvia [corrected to Lin, Sylvia ].

    Abstract

    Vancomycin, one of few effective treatments against methicillin-resistant Staphylococcus aureus, is nephrotoxic. The goals of this study were to (1) gain insights into molecular mechanisms of nephrotoxicity at the genomic level, (2) evaluate gene markers of vancomycin-induced kidney injury, and (3) compare gene expression responses after iv and ip administration. Groups of six female BALB/c mice were treated with seven daily iv or ip doses of vancomycin (50, 200, and 400 mg/kg) or saline, and sacrificed on day 8. Clinical chemistry and histopathology demonstrated kidney injury at 400 mg/kg only. Hierarchical clustering analysis revealed that kidney gene expression profiles of all mice treated at 400 mg/kg clustered with those of mice administered 200 mg/kg iv. Transcriptional profiling might thus be more sensitive than current clinical markers for detecting kidney damage, though the profiles can differ with the route of administration. Analysis of transcripts whose expression was changed by at least twofold compared with vehicle saline after high iv and ip doses of vancomycin suggested the possibility of oxidative stress and mitochondrial damage in vancomycin-induced toxicity. In addition, our data showed changes in expression of several transcripts from the complement and inflammatory pathways. Such expression changes were confirmed by relative real-time reverse transcription-polymerase chain reaction. Finally, our results further substantiate the use of gene markers of kidney toxicity such as KIM-1/Havcr1, as indicators of renal injury.

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    Curr Pharm Des. 2007;13(1):119-26.

    Aminoglycoside-induced ototoxicity.

    Selimoglu E.

    Source

    Inonu University, Department of Otorhinolaryngology, Malatya, Turkey. erolselimoglu@hotmail.com

    Abstract

    It has long been known that the major irreversible toxicity of aminoglycosides is ototoxicity. Among them, streptomycin and gentamicin are primarily vestibulotoxic, whereas amikacin, neomycin, dihydrosterptomycin, and kanamicin are primarily cochleotoxic. Cochlear damage can produce permanent hearing loss, and damage to the vestibular apparatus results in dizziness, ataxia, and/or nystagmus. Aminoglycosides appear to generate free radicals within the inner ear, with subsequent permanent damage to sensory cells and neurons, resulting in permanent hearing loss. Two mutations in the mitochondrial 12S ribosomal RNA gene have been previously reported to predispose carriers to aminoglycoside-induced ototoxicity. As aminoglycosides are indispensable agents both in the treatment of infections and Meniere's disease, a great effort has been made to develop strategies to prevent aminoglycoside ototoxicity. Anti-free radical agents, such as salicylate, have been shown to attenuate the ototoxic effects of aminoglycosides. In this paper, incidence, predisposition, mechanism, and prevention of aminoglycoside-induced ototoxicity is discussed in the light of literature data.

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    Antimicrob Agents Chemother. 2007 Mar;51(3):962-7. Epub 2006 Dec 28.

    Reversible inhibition of mitochondrial protein synthesis during linezolid-related hyperlactatemia.

    Garrabou G, Soriano A, L�pez S, Guallar JP, Giralt M, Villarroya F, Mart�nez JA, Casademont J, Cardellach F, Mensa J, Mir� O.

    Source

    Mitochondrial Research Laboratory, Muscle Research Unit, Internal Medicine Department, Hospital Clinic of Barcelona, Villarroel 170, 08036 Barcelona, Catalonia, Spain.

    Abstract

    The objective of the present study was to determine the mitochondrial toxicity mechanisms of linezolid-related hyperlactatemia. Five patients on a long-term schedule of linezolid treatment were studied during the acute phase of hyperlactatemia and after clinical recovery and lactate normalization following linezolid withdrawal. Mitochondrial studies were performed with peripheral blood mononuclear cells and consisted of measurement of mitochondrial mass, mitochondrial protein synthesis homeostasis (cytochrome c oxidase [COX] activity, COX-II subunit expression, COX-II mRNA abundance, and mitochondrial DNA [mtDNA] content), and overall mitochondrial function (mitochondrial membrane potential and intact-cell oxidative capacity). During linezolid-induced hyperlactatemia, we found extremely reduced protein expression (16% of the remaining content compared to control values [100%], P < 0.001) for the mitochondrially coded, transcribed, and translated COX-II subunit. Accordingly, COX activity was also found to be decreased (51% of the remaining activity, P < 0.05). These reductions were observed despite the numbers of COX-II mitochondrial RNA transcripts being abnormally increased (297%, P = 0.10 [not significant]) and the mitochondrial DNA content remaining stable. These abnormalities persisted even after the correction for mitochondrial mass, which was mildly decreased during the hyperlactatemic phase. Most of the mitochondrial abnormalities returned to control ranges after linezolid withdrawal, lactate normalization, and clinical recovery. Linezolid inhibits mitochondrial protein synthesis, leading to decreased mitochondrial enzymatic activity, which causes linezolid-related hyperlactatemia, which resolves upon discontinuation of linezolid treatment.

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    Nucleic Acids Symp Ser (Oxf). 2005;(49):253-4.

    Crystallographic studies of Homo sapiens ribosomal decoding A site complexed with aminoglycosides.

    Kondo J, Fran�ois B, Urzhumtsev A, Westhof E.

    Source

    Institut de Biologie Mol�culaire et Cellulaire, UPR9002 CNRS, Universit� Louis Pasteur, 15 rue Ren� Descartes, 67084 Strasbourg, France.

    Abstract

    Aminoglycosides are highly effective antibacterial drugs that decrease translation accuracy by binding to the aminoacyl-tRNA decoding site (A site) of 16S ribosomal RNA. On the other hand, they are highly toxic to mammals through kidney and ear-associated illnesses by binding to ribosomal A sites. To understand the mechanism of toxicity of aminoglycosides to mammals at atomic level, crystallographic studies have been carried out with a number of Homo sapiens mitochondrial and cytoplasmic A sites complexed with aminoglycosides. Several X-ray diffraction data sets were successfully collected. Initial phases of mitochondrial A site with tobramycin and cytoplasmic A site with paromomycin were derived by the molecular replacement method. Refinements of atomic parameters are now under progress.

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    Clin Infect Dis. 2005 Jun 15;40(12):e113-6. Epub 2005 May 3.

    Does linezolid cause lactic acidosis by inhibiting mitochondrial protein synthesis?

    Palenzuela L, Hahn NM, Nelson RP Jr, Arno JN, Schobert C, Bethel R, Ostrowski LA, Sharma MR, Datta PP, Agrawal RK, Schwartz JE, Hirano M.

    Source

    Department of Neurology, Columbia University College of Physicians and Surgeons, New York, USA.

    Abstract

    Linezolid, an oxazolidinone antibiotic, inhibits bacterial protein synthesis by binding to 23S ribosomal RNA (rRNA). We studied 3 patients who experienced lactic acidosis while receiving linezolid therapy. The toxicity may have been caused by linezolid binding to mitochondrial 16S rRNA. Genetic polymorphisms may have contributed to the toxicity in 2 patients.

    Supplemental Content

     
     

    Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2004 Dec;148(2):221-3.

    Influence of amphotericin B deoxycholate or amphotericin B colloidal dispersion on renal tubule epithelium in rat.

    Krejc�rov� L, Lauschov� I, Hork� D, Doubek M, Mayer J, Doubek J.

    Source

    Department of Histology and Embryology, Medicine Faculty Masaryk University Brno, Czech Republic. lkrejcir@med.muni.cz

    Abstract

    Amphotericin B deoxycholate (AmB) or Amphotericin B colloidal dispersion (ABCD) are used in clinics for the treatment of systemic fungal infections. The goal of our study was to compare the nephrotoxicity of these drugs in rat kidney. The effects of AmB and ABCD on the ultrastructure of the epithelium of renal tubules were studied and evaluated using morphometric and statistical methods. Two groups of 3 animals were established: group 1 was treated with AmB desoxycholate and group 2, to which ABCD was applied. AmB caused more than ABCD ultrastructural changes in the cytoplasm of the epithelial cells: damage to mitochondria, vacuolation of cytoplasm, and increased values of volume density of peroxisomes. However, we failed to observe significant differences in morphology and density of the other cell organelles. The proximal tubules seemed to be more sensitive to the nephrotoxic influence of both formulas than the distal tubules of rat kidney. Although, AmB causes more severe damage than ABCD, both drugs cause damage to renal tubuli.

    Supplemental Content

     
     

    Am J Physiol Renal Physiol. 2004 Apr;286(4):F617-24. Epub 2003 Nov 18.

    Gentamicin traffics retrograde through the secretory pathway and is released in the cytosol via the endoplasmic reticulum.

    Sandoval RM, Molitoris BA.

    Source

    Indiana Univ. School of Medicine, 950 West Walnut, R2-E251, Indianapolis, IN 46202, USA. bmolitor@iupui.edu

    Abstract

    Previous mechanisms describing how aminoglycosides exert their cellular toxicity, including lysosomal accumulation, rupture, and release, cannot account for the rapidity and extent of the observed subcellular and organ effects. Using immunoamplification techniques and colocalization with epitopes of the endoplasmic reticulum (ER), we report rapid retrograde transport of gentamicin to the ER. Additionally, exposure times of 2 and 4 h in LLC-PK1 cells produced cytosolic release and nuclear association. Cellular internalization and trafficking of aminoglycoside structural analogs, amine-containing cationic fluorescent dextrans of 3,000 molecular weight, corroborated these findings. However, identical anionic fluorescent dextrans, or larger cationic dextrans, of 10,000 molecular weight, failed to traverse from the ER into the cytosol or localize within the nucleus. These studies suggest that a pathway exists that transports internalized aminoglycosides, and other small-molecular-weight cationic compounds, in a retrograde manner through the Golgi complex and to the ER. From there, these compounds move into the cytosol for delivery throughout the cell. To quantify the potential toxic effects of cytosolic aminoglycoside release, experiments examining mitochondrial membrane potential in the continued presence of extracellular gentamicin were undertaken and demonstrated a significant reduction after 4 and 8 h. These observations provide a mechanism for the rapidly induced known cellular alterations, including aberrant vesicle fusion, mitochondrial toxicity/free radical generation, and decreased protein synthesis either by reduced transcription or translation after aminoglycoside exposure.

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    Mol Pharmacol. 2002 Jun;61(6):1348-58.

    A novel beta-lactam antibiotic activates tumor cell apoptotic program by inducing DNA damage.

    Smith DM, Kazi A, Smith L, Long TE, Heldreth B, Turos E, Dou QP.

    Source

    Drug Discovery Program, and the Department of Chemistry, College of Arts and Sciences, University of South Florida, Tampa, Florida 33612-9497, USA.

    Abstract

    Many of the anticancer drugs in current use are toxic and thus limited in their efficacy. It therefore becomes essential to develop novel chemotherapeutic agents with lower levels of toxicity. The beta-lactam antibiotics have been used for many years to treat bacterial infections with limited or no toxicity. Until now, it has never been shown that beta-lactams could kill tumor cells. Here, for the first time, we have discovered and characterized the apoptosis-inducing properties of a family of novel beta-lactam antibiotics against human leukemia, breast, prostate, and head-and-neck cancer cells. We found that one particular lead compound (lactam 1) with an N-methylthio group was able to induce DNA damage and inhibit DNA replication in Jurkat T cells within a 2-h treatment. This was followed by p38 mitogen-activated protein kinase activation, S phase arrest, and apoptotic cell death. p38 was found to be a central player in beta-lactam-induced apoptosis and resided downstream of DNA damage but upstream of caspase activation. Accompanying caspase-8 activation was cleavage of the pro-apoptotic Bcl-2 family protein Bid, and release of the mitochondrial cytochrome c. This was also associated with activation of caspase-9 and -3. Analogs of lactam 1 in which the N-methylthio group was replaced with other organothio chains exhibited progressive decreased potencies to induce DNA damage, p38 kinase activation, S phase arrest, and apoptosis, demonstrating requirement of the N-methylthio group. Because of the ease of synthesis and structural manipulation, we believe these beta-lactams may have the potential to be developed into anticancer agents.

    Supplemental Content

     
     

    Basic Clin Pharmacol Toxicol. 2008 Oct;103(4):349-53. Epub 2008 Jul 18.

    Chloramphenicol-induced oxidative stress in human neutrophils.

    P�ez PL, Becerra MC, Albesa I.

    Department of Pharmacy, Faculty of Chemical Sciences, National University of C�rdoba, C�rdoba, Argentina.

    Abstract

    The aim of this study was to evaluate the in vitro effect of chloramphenicol in order to determine its potential toxic effects on human neutrophils, by using assays of reactive oxygen species (ROS) determination, nitrite measurement and antioxidant systems. Chloramphenicol enabled the oxidative stress response of neutrophils and increased the ROS production at 2, 4, 8 and 16 microg/ml, while ROS generation decreased at high concentrations (32 microg/ml). The nitroblue tetrazolium assay shows that neutrophils incubated with chloramphenicol increased the intracellular ROS, with the extracellular production rising with a corresponding increase in antibiotic concentration. Enzymatic activities--superoxide dismutase, catalase and diaphorase enzymes--increased after chloramphenicol treatment, while the glutathione level decreased in neutrophils incubated with antibiotic. The results obtained in the present work suggest that the study of susceptibility to oxidative stress in neutrophils before chloramphenicol treatment could be adequate for in vitro toxicity screening.

    PMID: 18684218 [PubMed - indexed for MEDLINE]

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    J Enzyme Inhib Med Chem. 2008 Feb;23(1):144-8.

    Effects of some antibiotics on human erythrocyte glutathione reductase: an in vitro study.

    Senturk M, Kufrevioglu OI, Ciftci M.

    Department of Chemistry, Ataturk University, Erzurum, Turkey.

    Abstract

    Inhibitory effects of some antibiotics on purified human erythrocyte glutathione reductase were investigated. Human erythrocyte glutathione reductase was purified 2800-fold (29% yield) at 4 degrees C using 2', 5'-ADP Sepharose 4B affinity gel and Sephadex G-200 gel filtration chromatography. SDS polyacrylamide gel electrophoresis showed a single band for the enzyme. Imipenem, rifamycin, sulfanylacetamide, ceftazidime, chloramphenicol, seftriaxon, vancomycin, cefuroxime and ornidazole exhibited inhibitory effects but clindamycin, lincomycin, amoxicillin, amikacin exhibited activatory effects on the enzyme in vitro. The IC(50) values of imipenem, rifamycin, sulfanylacetamide, ceftazidime, chloramphenicol, seftriaxon, vancomycin, cefuroxime and ornidazole were 0.030, 0.146, 0.59, 2.476, 2.36, 2.88, 4.83, 15.43 and 19.632 mM, respectively, and the K(i) constants were 0.06 +/- 0.01, 0.275 +/- 0.10, 0.85 +/- 0.05, 3.59 +/- 0.51, 3.85 +/- 0.40, 3.71 +/- 0.60, 15.11 +/- 2.50, 23.50 +/- 2.94 and 28.49 +/- 6.50 mM, respectively. While imipenem, rifamycin, sulfanylacetamide, ceftazidime, chloramphenicol and seftriaxon cefuroxime and ornidazole showed competitive inhibition, vankomycine displayed noncompetitive inhibition.

    PMID: 18341267 [PubMed - indexed for MEDLINE]

    Supplemental Content

     

    Isoniazid induces oxidative stress, mitochondrial dysfunction and apoptosis in Hep G2 cells.

    Bhadauria S, Singh G, Sinha N, Srivastava S.

    Division of Toxicology, Central Drug Research Institute, Lucknow, India. smrati_bhadauria@hotmail.com

    Abstract

    Isoniazid (INH) continues to be a sheet anchor in treatment of tuberculosis, however its chronic administration is known to cause hepatotoxicity through a poorly defined mechanism. Ellucidation of mechanism underlying INH induced hepatotoxicity may be beneficial in devising ways to counteract toxic manifestations. In view of this concentration dependent effects INH were evaluated in hepatoma cell line (Hep-G2). INH exposure produced cytotoxic effects in Hep-G2 cells in a characteristic dose dependent manner. There was considerable cell detachment, loss of viability and alterations in cellular morphology that were indicative of toxic insult. We observed cell shrinkage at highest concentrations (88 microM) suggesting an involvement of apoptosis. This finding was substantiated by the flow cytometry data and DNA fragmentation analysis which clearly indicated that INH induced cytotoxicity, was being mediated by induction of apoptosis. Furthermore there was mitochondrial dysfunction as indicated by significant inhibition of MTT Reduction as compared to control at all the concentrations and depletion of cellular glutathione (GSH) content along with increased production of Reactive oxygen species (ROS). Collectively these findings led us to conclude that INH induced apoptosis in Hep-G2 cells is mediated by generation of oxidative stress.

    Toxicol Appl Pharmacol. 2006 Sep 1;215(2):158-67. Epub 2006 Apr 17.

    Bioactivation, protein haptenation, and toxicity of sulfamethoxazole and dapsone in normal human dermal fibroblasts.

    Bhaiya P, Roychowdhury S, Vyas PM, Doll MA, Hein DW, Svensson CK.

    Division of Pharmaceutics, College of Pharmacy, The University of Iowa, Iowa City, IA 52242, USA.

    Abstract

    Cutaneous drug reactions (CDRs) associated with sulfonamides are believed to be mediated through the formation of reactive metabolites that result in cellular toxicity and protein haptenation. We evaluated the bioactivation and toxicity of sulfamethoxazole (SMX) and dapsone (DDS) in normal human dermal fibroblasts (NHDF). Incubation of cells with DDS or its metabolite (D-NOH) resulted in protein haptenation readily detected by confocal microscopy and ELISA. While the metabolite of SMX (S-NOH) haptenated intracellular proteins, adducts were not evident in incubations with SMX. Cells expressed abundant N-acetyltransferase-1 (NAT1) mRNA and activity, but little NAT2 mRNA or activity. Neither NAT1 nor NAT2 protein was detected. Incubation of NHDF with S-NOH or D-NOH increased reactive oxygen species formation and reduced glutathione content. NHDF were less susceptible to the cytotoxic effect of S-NOH and D-NOH than are keratinocytes. Our studies provide the novel observation that NHDF are able to acetylate both arylamine compounds and bioactivate the sulfone DDS, giving rise to haptenated proteins. The reactive metabolites of SMX and DDS also provoke oxidative stress in these cells in a time- and concentration-dependent fashion. Further work is needed to determine the role of the observed toxicity in mediating CDRs observed with these agents.

    PMID: 16603214 [PubMed - indexed for MEDLINE]PMCID: PMC1615915Free PMC Article

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    J Biol Chem. 2006 Feb 10;281(6):3382-8. Epub 2005 Dec 14.

    Aminoglycosides decrease glutathione peroxidase-1 activity by interfering with selenocysteine incorporation.

    Handy DE, Hang G, Scolaro J, Metes N, Razaq N, Yang Y, Loscalzo J.

    Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. dhandy@rics.bwh.harvard.edu

    Erratum in:

    • J Biol Chem. 2009 Sep 11;284(37):25459.

    Abstract

    Cellular glutathione peroxidase is a key intracellular antioxidant enzyme that contains a selenocysteine residue at its active site. Selenium, a selenocysteine incorporation sequence in the 3'-untranslated region of the glutathione peroxidase mRNA, and other translational cofactors are necessary for "read-through" of a UGA stop codon that specifies selenocysteine incorporation. Aminoglycoside antibiotics facilitate read-through of premature stop codons in prokayotes and eukaryotes. We studied the effects of G418, an aminoglycoside, on cellular glutathione peroxidase expression and function in mammalian cells. Insertion of a selenocysteine incorporation element along with a UGA codon into a reporter construct allows for read-through only in the presence of selenium. G418 increased read-through in selenium-replete cells as well as in the absence of selenium. G418 treatment increased immunodetectable endogenous or recombinant glutathione peroxidase but reduced the specific activity of the enzyme. Tandem mass spectrometry experiments indicated that G418 caused a substitution of l-arginine for selenocysteine. These data show that G418 can affect the biosynthesis of this key antioxidant enzyme by promoting substitution at the UGA codon.

    PMID: 16354666 [PubMed - indexed for MEDLINE]PMCID: PMC1472404Free PMC Article

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    Drug Chem Toxicol. 2005;28(4):433-45.

    Effects of some antibiotics on activity of glucose-6-phosphate dehydrogenase from human erythrocytes in vitro and effect of isepamicin sulfate on activities of antioxidant enzymes in rat erythrocytes.

    Ozmen I, K�frevioğlu OI, Gul M.

    Biotechnology Application and Research Center, Atat�rk University, Erzurum, Turkey. iozmen@atauni.edu.tr

    Abstract

    The purpose of this study was to investigate effects of some antibiotics on glucose-6-phosphate dehydrogenase (G6PD), antioxidant enzymes, and malondialdehyde (MDA). Initially, for in vitro studies, G6PD was purified from human erythrocyte, 9811-fold in a yield of 42.4% by using ammonium sulfate precipitation and 2',5' ADP-Sepharose 4B affinity gel. The purified enzyme showed a single band on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The effects of four different antibiotics (isepamicin sulfate, meropenem, chloramphenicol, and thiamphenicol glisinat hydrochloride) were investigated on the purified enzyme. K(i) value and type of inhibition were determined by means of Lineweaver-Burk graphs and regression analysis graphs. Isepamicin sulfate inhibited the enzyme activity (I(50) value, 2.1 mM; K(i) value, 1.7 mM), whereas thiamphenicol glisinat hydrochloride activated the G6PD dose dependently. Other drugs showed no inhibition and activation effect. In addition, the effects of isepamicin sulfate on the activities of G6PD, glutathione reductase (GR), superoxide dismutases (SOD), glutathione peroxidase (GPx), catalase (CAT), and glutathione S-transferase (GST) and MDA concentrations were examined in Sprague-Dawley rat erythrocytes in vivo. A marked alteration in the activities of these enzymes and MDA levels may be the result of oxidative stress in the rats receiving isepamicin sulfate.

    PMID: 16298874 [PubMed - indexed for MEDLINE]

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    Antimicrob Agents Chemother. 2005 Sep;49(9):3784-8.

    Assessment of effective renal plasma flow, enzymuria, and cytokine release in healthy volunteers receiving a single dose of amphotericin B desoxycholate.

    Pai MP, Norenberg JP, Telepak RA, Sidney DS, Yang S.

    College of Pharmacy, MSC09 5360, University of New Mexico, Albuquerque, NM 87131-0001, USA. apai@salud.unm.edu.

    Erratum in:

    • Antimicrob Agents Chemother. 2005 Oct;49(10):4427.

    Abstract

    The present study assessed potential subclinical markers of amphotericin B (AmB)-related nephrotoxicity and infusion-related reactions (IRR). Subjects were pretreated with diphenhydramine and acetaminophen and received a 500-ml bolus infusion of 0.9% sodium chloride prior to each effective renal plasma flow (ERPF) assessment. ERPF was measured before and after administration of a single 0.25-mg/kg intravenous AmB dose using technetium-99m mercaptoacetyltriglycine. Blood was collected before and 3 h after AmB infusion for tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) plasma concentrations. Overnight 12-h urine collections were performed before administration of AmB and for 2 nights after administration of AmB and analyzed for alpha and pi glutathione-S-transferases (GSTalpha and GSTpi, respectively) and N-acetyl-beta-d-glucosaminidase (NAG). Six men and six women with mean +/- standard deviation (SD) ages of 24.8 +/- 5.3 and 28.0 +/- 8.5 years, respectively, were studied. Baseline serum creatinine values were within the normal range and were unaltered after administration of AmB. The mean +/- SD decrease in ERPF after administration of AmB was significant (P < 0.05) in males (15.7 +/- 8.1%) but not females (9.5 +/- 14.0%). The GSTpi and GSTalpha indices increased significantly (P < 0.05) by two to fourfold and returned to baseline in males but were unaltered in females. NAG indices were unaffected by AmB. Six patients experienced an IRR that was associated with increased TNF-alpha (P < 0.05) but not IL-1beta (P = 0.09). These results suggest a potential sex-related difference in AmB-induced nephrotoxicity and provide a rationale for use of ERPF, urine GST, and TNF-alpha as subclinical markers of polyene-induced toxicity.

    PMID: 16127053 [PubMed - indexed for MEDLINE]PMCID: PMC1195419Free PMC Article

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    Neuroscience. 2005;133(4):959-67.

    Involvement of mitochondrial potential and calcium buffering capacity in minocycline cytoprotective actions.

    Fernandez-Gomez FJ, Galindo MF, Gomez-Lazaro M, Gonz�lez-Garc�a C, Ce�a V, Aguirre N, Jord�n J.

    Departamento de Ciencias M�dicas, Facultad de Medicina, Universidad de Castilla-La Mancha, Avenida Almansa, s/n, 02006 Albacete, Spain.

    Abstract

    Minocycline, a semisynthetic derivative of tetracycline, displays beneficial activity in neuroprotective in models including, Parkinson disease, spinal cord injury, amyotrophic lateral sclerosis, Huntington disease and stroke. The mechanisms by which minocycline inhibits apoptosis remain poorly understood. In the present report we have investigated the effects of minocycline on mitochondria, due to their crucial role in apoptotic pathways. In mitochondria isolated suspensions, minocycline failed to block superoxide-induced swelling but was effective in blocking mitochondrial swelling induced by calcium. This latter effect might be mediated through dissipation of mitochondrial transmembrane potential and blockade of mitochondrial calcium uptake. Consistently, minocycline fails to protect SH-SY5Y cell cultures against reactive oxygen species-mediated cell death, including malonate and 6-hydroxydopamine treatments, but it is effective against staurosporine-induced cytotoxicity. The effects of this antibiotic on mitochondrial respiratory chain complex were also analyzed. Minocycline did not modify complex IV activity, and only at the higher concentration tested (100 microM) inhibited complex II/III activity. Other members of the minocycline antibiotic family like tetracycline failed to induce these mitochondrial effects.

    PMID: 15964487 [PubMed - indexed for MEDLINE]

    Supplemental Content

     
     

    J Toxicol Sci. 2008 Feb;33(1):85-96.

     Links

      An aminoglycoside antibiotic gentamycin induces oxidative stress, reduces antioxidant reserve and impairs spermatogenesis in rats.

      Narayana K.

      Department of Anatomy, Faculty of Medicine, HSC, Kuwait University, Safat, Kuwait. narayana68@yahoo.com

      Gentamycin (GS) is an aminoglycoside antibiotic used to treat infections of various Gram-negative organisms. The present study was designed to investigate the effects of GS on oxidative stress, antioxidant levels, testicular structure and sperm parameters in the rat. Adult Wistar rats (12 week old; N=7/group) were treated (i. p.) with 0 mg/kg, 3 mg/kg and 5 mg/kg for 10 days at an interval of 24 hr between subsequent treatments. Animals were sacrificed on days 1 and 35 after the last treatment, and the reproductive organs were removed and weights of testis and seminal vesicle were recorded. The right testis was processed for light microscopic analysis. The left testis was homogenized and step 19 spermatids were counted to determine the daily sperm production (DSP) and daily abnormal sperm production (DASP). The sperm count, sperm motility and incidence of abnormal sperms were estimated in the epididymis. In testicular sections, along with the evaluation of qualitative changes, the seminiferous tubule diameter (STD) and the epithelial height (SE) were measured. The incidence of stage XIV tubules in testicular sections, meiotic figures and step 14 spermatids/stage XIV tubule, and step 19 spermatids/stage VII tubule were estimated. Intra-testicular levels of superoxide anion, lipid peroxidation and antioxidants-superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and ascorbic acid were measured. GS did not affect the body weight, but the testis weight and DSP were decreased at 5 mg/kg dose-level on both days (p<0.05), and the weight of seminal vesicle decreased on day 35 at both dose-levels. The DASP was increased in a dose-dependent manner (p<0.05) on days 1 and 35 at both dose-levels. The sperm count was decreased at both dose-levels on day 35, whereas the sperm motility was decreased and sperm abnormality was increased on day 1 at 5 mg/kg and on day 35 at both dose-levels. GS induced structural changes such as sloughing of seminiferous epithelium, vacuoles and gaps in the epithelium, nuclear pyknosis and atrophic changes in a few tubules. The tubular shrinkage was observed as indicated by decreased STD and SE on both days at 5 mg/kg dose-level. Incidence of stage XIV tubules and step 19 spermatids/stage VII tubule decreased on all time points at all dose-levels, whereas the step 14 spermatids and meiotic figures decreased on day 35 at both dose-levels (p<0.05). The free radical- superoxide anion concentration was significantly increased on day 1 in a dose-dependent pattern (p<0.05). However, activities of all 3 enzymatic antioxidants and ascorbic acid level decreased in a dose-dependent pattern on day 1 (p<0.05), except the GPx, which was also decreased on day 35 at 5 mg/kg dose-level. There was a significant rise in the thiobarbituric acid reactive substances on day 1 indicating increased lipid peroxidation in the testis. In conclusion, GS induces an oxidative stress-status in the testis by increasing free radical formation and lipid peroxidation, and by decreasing the antioxidant reserves. These biochemical changes manifest as structural and cytotoxic changes in the testis. Further, GS also affects the spermatozoa by affecting their number, motility and morphology.

      PMID: 18303187 [PubMed - indexed for MEDLINE] 

    Free Radic Biol Med. 2010 Dec 1;49(11):1666-73. Epub 2010 Aug 31.

    An oxidative environment promotes growth of Mycobacterium abscessus.

    Oberley-Deegan RE, Rebits BW, Weaver MR, Tollefson AK, Bai X, McGibney M, Ovrutsky AR, Chan ED, Crapo JD.

    Source

    Department of Medicine, National Jewish Health, Denver, CO 80206, USA. oberleyr@njc.org

    Abstract

    Mycobacterium abscessus infections, particularly those causing chronic lung diseases, are becoming more prevalent worldwide. M. abscessus infections are difficult to treat because of antibiotic resistance. Thus, new treatment options are urgently needed. M. abscessus is an intracellular pathogen that primarily infects macrophages and fibroblasts. Because this bacterium has only recently been identified as a separate species, very little is known about M. abscessus-host interactions and how M. abscessus growth is regulated. Oxidative stress has long been shown to inhibit the growth of bacterial organisms. However, some intracellular bacteria, such as Mycobacterium tuberculosis, grow well in oxidizing environments. In this study, we show that M. abscessus infection causes the host cell environment to become more oxidizing. Furthermore, we show that a more oxidizing environment leads to enhanced growth of M. abscessus inside macrophages. In the presence of antioxidants, MnTE-2-PyP (chemical name: manganese(II) meso-tetrakis-(N-methylpyridinium-2-yl) porphyrin) or N-acetyl-l-cysteine, M. abscessus growth is inhibited. These results lead us to postulate that antioxidants may aid in the treatment of M. abscessus infections.

    Copyright � 2010 Elsevier Inc. All rights reserved.

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