The influence of atracurium, cisatracurium, and mivacurium on the proliferation of two human cell lines in vitro.
We tested the influence of atracurium and cisatracurium (final concentrations: 0, 0.96, 3.2, 9.6, 32, and 96 microM) on proliferation of human cells (hepatoma HepG2 cells and human umbilical vein endothelial cells) in vitro. In additional experiments, glutathione, N-acetylcysteine, or carboxyl esterase was added before the addition of either relaxant. The number of cells counted after 72 h of incubation was expressed as a percentage of the mean cell number in wells incubated without additives. Atracurium and cisatracurium progressively decreased cell proliferation in a concentration-dependent pattern. With human umbilical vein endothelial cells, atracurium or cisatracurium (3.2 microM) decreased the cell count to 67.7 % (SD, 14.8%) and 50% (SD, 8.6%), respectively. Cell proliferation was not inhibited by mivacurium. The results were similar to those with HepG2 cells. Glutathione, N-acetylcysteine, and carboxyl esterase partially reversed the effects of atracurium and cisatracurium. When incubated in a buffer with glutathione, atracurium decreased the number of glutathione-sulfhydryl groups. The findings that atracurium and cisatracurium inhibit proliferation of human cell lines in vitro, but that mivacurium does not, and that this effect is alleviated by glutathione and N-acetylcysteine, as well as by the carboxyl esterase, indicate that the inhibition may be caused by the reactive acrylate metabolites.
Amann
A
A
Department of Anesthesiology, Leopold-Franzens-University of Innsbruck, Austria. anton.amann@uibk.ac.at
Rieder
J
J
Fleischer
M
M
Niedermüller
P
P
Hoffmann
G
G
Amberger
A
A
Marth
C
C
Nigrovic
V
V
Pühringer
F
F
D000111:Acetylcysteine / Q000494:pharmacology; D001279:Atracurium / Q000031:analogs & derivatives / Q000494:pharmacology*; D002265:Carboxylic Ester Hydrolases / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology; D000077590:Mivacurium; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*
D016166:Free Radical Scavengers; D007546:Isoquinolines; D003473:Neuromuscular Nondepolarizing Agents; D001279:Atracurium; D000077590:Mivacurium; D002265:Carboxylic Ester Hydrolases; D005978:Glutathione; C101584:cisatracurium; D000111:Acetylcysteine