Inhibition of kidney lysosomal phospholipases A and C by aminoglycoside antibiotics: possible mechanism of aminoglycoside toxicity.

Hostetler, Karl Y.; Häll, Lena

doi:10.1073/pnas.79.5.1663

Cited by 84 publications

(39 citation statements)

References 28 publications

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“…On the other hand, methylation of all amino groups drastically decreases the inhibitory potency (kanamycin A versus tetra-or octa-N-methylkanamycin A). (15).…”

Section: Resultismentioning

confidence: 99%

“…It was also reported that aminoglycosides accumulate in the lysosomes (18,35,40). Recently, another group of investigators and ourselves (15,24) showed independently that lysosomal phospholipases are inhibited in vitro by aminoglycosides. The concentrations needed to produce this inhibition (0 to 500 ,ug/ml) are in the range of those observed in the lysosomes of fibroblasts (3) or proximal tubular cells (24,29).…”

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confidence: 99%

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Inhibition of lysosomal phospholipases by aminoglycoside antibiotics: in vitro comparative studies

Carlier¹,

Laurent²,

Claes³

et al. 1983

Antimicrob Agents Chemother

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Aminoglycoside antibiotics induce an early and characteristic lysosomal phospholipidosis in cultured fibroblasts and in kidney tubular cells. We have recently demonstrated an inhibition of lysosomal phospholipases A1 and A2 by gentamicin and amikacin in vitro. In vivo, gentamicin decreases the activity of phospholipase A1 (Laurent et al., Biochem. Pharmacol. 31:3861-3870, 1982). In the present study, we examined 14 aminoglycosides for in vitro inhibition of phospholipases. To mimic the situation prevailing in lysosomes, the enzymatic activities were assayed with phospholipid vesicles (liposomes) with a composition similar to that of lysosomal phospholipids (phosphatidylcholine, sphingomyelin, phosphatidylinositol, cholesterol; 4:4:3:5.5, molar ratio). We measured the hydrolysis of 1-palmitoyl-2-[1-14C]oleoyl phosphatidylcholine contained in the liposomes by a soluble fraction of highly purified lysosomes isolated from rat liver. Similar IC50s (concentrations causing 50% inhibition of enzymatic activity) were observed for dibekacin, gentamicin (with no major difference between C1, Cla, or C2), netilmicin, tobramycin, and kanamycin B. Sisomicin was slightly more inhibitory. Kanamycin A, N1-(L-4-amino-2-hydroxy-l-oxobutyl)dibekacin, and amikacin showed increasing IC50s. Streptomycin caused the least inhibition. Octa-and tetramethylkanamycin A are much less inhibitory than the parent drug. These results point to the number, the nature, and the respective positions of the cationic groups as essential determinants in causing inhibition of phospholipid breakdown. The binding of three aminoglycosides (gentamicin, amikacin, streptomycin) to the liposomes at pH 5.4 was also measured by gel permeation and was found to be related to the respective inhibitory potency of each drug. Insofar as lysosomal phospholipidosis is an early sign of intoxication by aminoglycosides, these results may serve as a basis for the development or screening of less toxic compounds in this class of antimicrobial agents.Aminoglycoside antibiotics are nephrotoxic (2). The earliest and most conspicuous alteration induced by these drugs in kidney ultrastructure is the accumulation of lamellar, osmiophilic material (myeloid bodies) in the lysosomes of proximal tubular cells (22). The characteristic periodic pattern of myeloid bodies, made of concentric layers at a 5-nm distance, suggests that they are made of polar lipids. In cultured fibroblasts exposed to gentamicin (3), as well as in the kidney cortex of treated animals (5, 10, 24), a significant increase in total lipid phosphorus has been observed. The studies with fibroblasts (3) have demonstrated a direct correlation between the accumulation of myeloid bodies in lysosomes and the increase of cell lipid phosphorus. Moreover, each micromole excess of phospholipid was shown to correspond to a volume of 1.8 pl of myeloid bodies, a figure similar to that found for multilamellar liposomes (artificial structures made of concentric layers of phospholipids [36]).Accumulation of phospholipids in the lyso...

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“…On the other hand, methylation of all amino groups drastically decreases the inhibitory potency (kanamycin A versus tetra-or octa-N-methylkanamycin A). (15).…”

Section: Resultismentioning

confidence: 99%

mentioning

confidence: 99%

Inhibition of lysosomal phospholipases by aminoglycoside antibiotics: in vitro comparative studies

Carlier¹,

Laurent²,

Claes³

et al. 1983

Antimicrob Agents Chemother

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“…In the process, the contents of the liposome are released (11). Gentamicin is not metabolized in the body, and this highly charged antibiotic is a potent inhibitor of mammalian phospholipases (4,14). In itself, this is unlikely to adversely affect the liver or spleen, as tissue macrophages are renewed from the bone marrow at a high rate.…”

Section: Discussionmentioning

confidence: 99%

Successful treatment using gentamicin liposomes of Salmonella dublin infections in mice

Fierer

Hatlen

Lin

et al. 1990

Antimicrob Agents Chemother

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Gentamicin entrapped within stable multilamellar liposomes was used to treat mice after they were infected per os with Salmonella dublin. Of 10 mice, 8 survived after a single intravenous (i.v.) injection of 2 mg of gentamicin liposomes per kg compared with 0 of 10 treated with the same amount of free gentamicin. AU mice survived after treatment with a single i.v. or intraperitoneal injection of 20 mg of gentamicin liposomes per kg, whereas that dose of free drug was completely ineffective and caused neuromuscular paralysis when injected rapidly i.v. In mice treated with gentamicin liposomes, there was a steady decrease in the number of salmonellae in spleens for 2 weeks after treatment. High concentrations of gentamicin were present in the spleen for at least 10 days after treatment. Although gentamicin was not detected in the mesenteric lymph nodes of mice treated with gentamicin liposomes, bacterial counts in the nodes also decreased over time. Small numbers of bacteria remained viable in the mesenteric lymph nodes and Peyer's patches but not in the spleens of mice treated with 20 to 80 mg/kg. Mice treated with doses of gentamicin liposomes as high as 80 mg/kg showed only a transient increase in blood urea nitrogen and no rise in serum creatinine. These results confirm that gentamicin in liposomes is less toxic in mice than is free gentamicin and is extremely effective-therapy for disseminated SalmoneUla infections in mice.

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“…Gentamicin has been shown to enhance the generation of superoxide anion and hydrogen peroxide by renal cortical mitochondria (15). It has been assumed that GM inhibits the activity of lysosomal phospholipase in proximal tubular epithelial cells (28). Because of the GM nephrotoxicity, tubular cells are damaged and phospholipidosis occurs in the damaged tubular cells.…”

Section: Discussionmentioning

confidence: 99%

“…The various HSP70s all have binding specificity for hydrophobic peptides, but the presence of certain amino acid patterns may vary from compartment to compartment (28,29). The peptides are bound in an extended conformation and a preferred pattern of certain aliphatic and aromatic residues at alternating positions (12).…”

Section: Discussionmentioning

confidence: 99%

73-kDa Molecular Chaperone HSP73 Is a Direct Target of Antibiotic Gentamicin

Miyazaki

Sagawa

Honma

et al. 2004

Journal of Biological Chemistry

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Although gentamicin (GM) has been used widely as an antibiotic, the specific binding protein of the drug has not yet been understood sufficiently. Here we show that GM specifically associates with the 73-kDa molecular chaperone HSP73 and reduces its chaperone activity in vitro. In the present study, we investigated GM-specific binding proteins using a GM-affinity column and porcine kidney cytosol. After washing the column, only the 73-kDa protein was eluted from the column by the addition of 10 mM GM. None of the other proteins were found in the eluant. Upon immunoblotting, the protein was identical to HSP73. Upon CD spectrum analysis, the binding of GM to HSP73 resulted in a conformational change in the protein. Although HSP73 prevents aggregation of unfolded rhodanese in vitro, the chaperone activity of HSP73 was suppressed in the presence of GM. Using limited proteolysis of HSP73 by TPCK-trypsin, the GM binding site is a COOH-terminal for one third of the protein known to be a peptide-binding domain. During immunohistochemistry, HSP73 and GM were co-localized in enlarged lysosomes of rat kidneys with GM-induced acute tubular injury in vivo. Our results suggest that the specific association between HSP73 and GM may reduce the chaperone activity of HSP73 in vitro and/or in vivo, and this may have an interaction with GM toxicity in kidneys with GM-induced acute tubular injury.

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Inhibition of kidney lysosomal phospholipases A and C by aminoglycoside antibiotics: possible mechanism of aminoglycoside toxicity.

Cited by 84 publications

References 28 publications

Inhibition of lysosomal phospholipases by aminoglycoside antibiotics: in vitro comparative studies

Inhibition of lysosomal phospholipases by aminoglycoside antibiotics: in vitro comparative studies

Successful treatment using gentamicin liposomes of Salmonella dublin infections in mice

73-kDa Molecular Chaperone HSP73 Is a Direct Target of Antibiotic Gentamicin

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