Propylene glycol-mediated cell injury in a primary culture of human proximal tubule cells.
Propylene glycol (propane-1,2-diol; PD) is a widely used solvent for intravenous drugs. Clinical studies have reported serious side effects, including the development of renal insufficiency in patients receiving PD as drug vehicle. Despite such clinical reports, the data on the toxicity of PD in isolated renal cells are limited. Using primary cultured human proximal tubule (HPT) cells as an in vitro model, we have previously shown the acute toxic effects of PD in HPT cells (Morshed et al., Fundam. Appl. Toxicol. 23, 38-43, 1994). Since most cases of clinical toxicity are noted after prolonged administration of PD, the current studies were designed to investigate the toxicity of repeated exposure of PD in HPT cells. The onset of toxicity was determined using 10-50 mM racemic, sinister, and rectus PD (rac-, S-, and R-PD, respectively) for periods up to 6 days. Cytotoxicity was noted by decreases in thymidine incorporation, in mitochondrial metabolic activity, and in lysosomal accumulation of neutral red. Exposure of HPT cells to 50 mM PD produced toxic responses, while at 10 mM, responses were not significantly greater than those of osmotic controls. The toxicity was caused by a PD-specific mechanism and by a secondary mechanism without any enantiomeric specificity. The HPT cell toxicity was associated with a 35% increase in cellular thiobarbituric acid-reactive substances and a 20% decrease in glutathione. These findings suggest the development of a mild, subacute toxicity in normally proliferating HPT cells at concentrations that could be achieved in human plasma when PD is used as a drug vehicle.
Department of Pharmacology and Therapeutics, Louisiana State University Medical Center, Shreveport 71130, USA.
K M
KM
Morshed
S K
SK
Jain
K E
KE
McMartin
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009499:Neutral Red / Q000493:pharmacokinetics*; D019946:Propylene Glycol / Q000633:toxicity*; D013237:Stereoisomerism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism*; D013997:Time Factors
D017392:Thiobarbituric Acid Reactive Substances; D009499:Neutral Red; D019946:Propylene Glycol; D005978:Glutathione; D013936:Thymidine