title: Chloroacetaldehyde- and acrolein-induced death of human proximal tubule cells.
abstract: Ifosfamide (ifo) is a commonly used drug in chemotherapy. It is metabolized to acrolein (acro) and chloroacetaldehyde (CAA), which are thought to be responsible for renal side effects. We studied the effects of ifo and cyclophosphamide (cyclo) as well as their metabolites, acro and CAA, on cellular protein content, necrosis, apoptosis and cytosolic calcium concentration using a human proximal tubule cell line. The protein content decreased during acro or CAA administration (15 to 300 micromol/l), but not during ifo or cyclo exposure over a time period of up to 72 h. Mild apoptosis was induced only by high acro (150, 300 micromol/l) and low CAA concentrations (15, 75 micromol/l) and only in a narrow time window (24 h). Necrosis was increased after exposure to acro or CAA at all concentrations. CAA was more potent than acro. Ifo and cyclo did not induce necrosis or apoptosis. Glutathione abolished CAA-induced cell death. Cytosolic calcium concentrations increased after acro or CAA administration and showed an oscillating pattern. Cytosolic Ca(2+) chelation did not prevent necrosis. We conclude that neither ifo nor cyclo induce cell damage, but that their metabolites acro and CAA induce cell death. This cell death occurs mainly by necrosis and not by apoptosis.
authors.affiliation: Institute of Physiology, University of Würzburg, Röntgenring 9, 97070 Würzburg, Germany. gerald.schwerdt@mail.uni-wuerzburg.de
authors.forename: Gerald
authors.initials: G
authors.lastname: Schwerdt
authors.forename: Nader
authors.initials: N
authors.lastname: Gordjani
authors.forename: Andreas
authors.initials: A
authors.lastname: Benesic
authors.forename: Ruth
authors.initials: R
authors.lastname: Freudinger
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wollny
authors.forename: Antje
authors.initials: A
authors.lastname: Kirchhoff
authors.forename: Michael
authors.initials: M
authors.lastname: Gekle
mesh_terms: D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000494:pharmacology; D000171:Acrolein / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D005978:Glutathione / Q000494:pharmacology*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects*; D010084:Oxidation-Reduction
chemical_list: D000171:Acrolein; C004656:chloroacetaldehyde; D005978:Glutathione; D000079:Acetaldehyde