title: HWA-448 reduces gentamicin toxicity in LLC-PK1 cells.
abstract: An LLC-PK1 cell culture model was used to evaluate for a direct protective effect of the pentoxifylline analogue HWA-448 in gentamicin nephrotoxicity at the cellular level. Cells exposed to 2 mM gentamicin for 6 days displayed a significant decrease in specific activities of leucine aminopeptidase, NaK ATPase, and N-acetyl glucosaminidase, and an increase in total cellular phospholipids (P < .05). Concomitant exposure to 0.125 mM HWA-448, a dose that did not alter cellular enzymes or total phospholipids under physiologic conditions, prevented the alterations in marker enzymes and total phospholipids induced by gentamicin (P < .05). Gentamicin binding and uptake studies revealed 0.125 mM HWA-448 had no effect on LLC-PK1 cell plasma membrane binding or cellular gentamicin uptake. We conclude that HWA-448 ameliorates gentamicin-induced alterations in LLC-PK1 cell enzymes and phospholipids by a mechanism independent of plasma membrane binding or cellular uptake.
authors.affiliation: Department of Pediatrics, Children's Hospital, University of Colorado Medical Center, Denver, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Ford
authors.forename: R E
authors.initials: RE
authors.lastname: Thieme
authors.forename: C A
authors.initials: CA
authors.lastname: Lamp
authors.forename: S J
authors.initials: SJ
authors.lastname: Covington
authors.forename: B A
authors.initials: BA
authors.lastname: Molitoris
mesh_terms: D000818:Animals; D004347:Drug Interactions; D005839:Gentamicins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D018374:LLC-PK1 Cells; D008954:Models, Biological; D010431:Pentoxifylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013552:Swine
chemical_list: D005839:Gentamicins; C061298:torbafylline; D000254:Sodium-Potassium-Exchanging ATPase; D010431:Pentoxifylline