Polyaspartic acid inhibits gentamicin-induced perturbations of phospholipid metabolism.
We investigated whether polyaspartic acid (PAA) can inhibit aminoglycoside-induced perturbations of phospholipid metabolism in cultured renal cells of opossum and rabbit and examined the mechanism involved. Cells incubated in medium containing gentamicin (10(-3) M) manifested a time-dependent increase in total phospholipid in association with the appearance of lysosomal myeloid bodies, impaired degradation of phospholipid, and disruption of the phosphatidylinositol (PI) cascade in response to bradykinin stimulation. These alterations of phospholipid metabolism were either completely or almost completely prevented in cells grown in medium containing gentamicin (10(-3) M) and PAA (3 x 10(-4) M, mol wt 11,000) even though PAA did not inhibit the cellular accumulation of gentamicin (40 +/- 1 vs. 42 +/- 1 micrograms/mg protein). In other in vitro studies, we demonstrated that gentamicin depressed the permeability of phosphatidylcholine (PC)/PI liposomes to glycerol and promoted liposomal aggregation. Both effects were blocked by prior addition of PAA. Methylene blue, a cationic dye, was shown to form an electrostatic complex with PAA; gentamicin competitively displaced methylene blue bound to PAA. Our results support the conclusion that the protective effect of PAA is related to its ability to serve as an anionic substrate that electrostatically binds aminoglycoside antibiotics and, thereby, prevents these polycationic drugs from interacting electrostatically with anionic phospholipid of cell membranes.
Ramsammy
L
L
Department of Medicine, State University of New York, Stony Brook 11794.
Josepovitz
C
C
Lane
B
B
Kaloyanides
G J
GJ
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005839:Gentamicins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D007700:Kinetics; D008081:Liposomes; D010455:Peptides / Q000494:pharmacology*; D010713:Phosphatidylcholines; D010716:Phosphatidylinositols; D010743:Phospholipids / Q000378:metabolism*
D005839:Gentamicins; D008081:Liposomes; D010455:Peptides; D010713:Phosphatidylcholines; D010716:Phosphatidylinositols; D010743:Phospholipids; C017645:polyaspartate; D001920:Bradykinin