Biomaterial Database

Inhibition of kidney lysosomal phospholipases A and C by aminoglycoside antibiotics: possible mechanism of aminoglycoside toxicity. 1982

K Y Hostetler, and L B Hall

Nephrotoxicity is an important side effect of aminoglycoside antibiotics, which are used to control infections caused by Gram-negative bacteria. Accumulation of aminoglycosides and phospholipids in the lysosomes is a prominent and early feature of aminoglycoside nephrotoxicity and is characterized histologically by the presence of numerous multilamellar bodies in kidney proximal tubule cells. Previous studies have shown that the drug-induced phospholipid fatty liver in man and animals is due to concentration of certain cationic amphiphilic drugs in lysosomes with inhibition of lysosomal phospholipases. It seemed possible that this mechanism might also explain the elevated levels of phospholipid and increased numbers of multilamellar bodies reported in the kidney cortex in aminoglycoside nephrotoxicity. In this study, subcellular localization of acid phospholipases A and C has been shown to be lysosomal in rat kidney cortex. A soluble lysosomal protein fraction was isolated and found to contain both phospholipase A and phospholipase C activity. Streptomycin did not inhibit the release of fatty acids from [3H]dioleoylphosphatidylcholine. However, amikacin, dibekacin, gentamicin, and tobramycin inhibited both phospholipase A and phospholipase C. Our results suggest that the accumulation of phospholipids in lysosomes of kidney cortex, an early and pervasive feature of acute aminoglycoside nephrotoxicity, is due to inhibition of lysosomal phospholipases.

UI	MeSH Term	Description	Entries
D007668	Kidney	Body organ that filters blood for the secretion of URINE and that regulates ion concentrations.	Kidneys
D008247	Lysosomes	A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes MEMBRANE FUSION. (From Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed).	Autolysosome,Autolysosomes,Lysosome
D008297	Male		Males
D010738	Type C Phospholipases	A subclass of phospholipases that hydrolyze the phosphoester bond found in the third position of GLYCEROPHOSPHOLIPIDS. Although the singular term phospholipase C specifically refers to an enzyme that catalyzes the hydrolysis of PHOSPHATIDYLCHOLINE (EC 3.1.4.3), it is commonly used in the literature to refer to broad variety of enzymes that specifically catalyze the hydrolysis of PHOSPHATIDYLINOSITOLS.	Lecithinase C,Phospholipase C,Phospholipases, Type C,Phospholipases C
D010740	Phospholipases	A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-.	Lecithinases,Lecithinase,Phospholipase
D010741	Phospholipases A	Phospholipases that hydrolyze one of the acyl groups of phosphoglycerides or glycerophosphatidates.
D000617	Aminoglycosides	Glycosylated compounds in which there is an amino substituent on the glycoside. Some of them are clinically important ANTIBIOTICS.	Aminoglycoside
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D000900	Anti-Bacterial Agents	Substances that inhibit the growth or reproduction of BACTERIA.	Anti-Bacterial Agent,Anti-Bacterial Compound,Anti-Mycobacterial Agent,Antibacterial Agent,Antibiotics,Antimycobacterial Agent,Bacteriocidal Agent,Bacteriocide,Anti-Bacterial Compounds,Anti-Mycobacterial Agents,Antibacterial Agents,Antibiotic,Antimycobacterial Agents,Bacteriocidal Agents,Bacteriocides,Agent, Anti-Bacterial,Agent, Anti-Mycobacterial,Agent, Antibacterial,Agent, Antimycobacterial,Agent, Bacteriocidal,Agents, Anti-Bacterial,Agents, Anti-Mycobacterial,Agents, Antibacterial,Agents, Antimycobacterial,Agents, Bacteriocidal,Anti Bacterial Agent,Anti Bacterial Agents,Anti Bacterial Compound,Anti Bacterial Compounds,Anti Mycobacterial Agent,Anti Mycobacterial Agents,Compound, Anti-Bacterial,Compounds, Anti-Bacterial
D013329	Structure-Activity Relationship	The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.	Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships