Pathobiological effects of acrolein in cultured human bronchial epithelial cells.
The ability of the highly reactive aldehyde acrolein to affect growth, membrane integrity, differentiation, and thiol status and to cause DNA damage has been studied at serum- and thiol-free conditions using cultured human bronchial epithelial cells. Acrolein markedly decreases colony survival at 3 microM whereas about 10-fold higher concentrations are required to increase membrane permeability, measured as uptake of trypan blue dye. Acrolein at micromolar concentrations also causes epithelial cells to undergo squamous differentiation as indicated by decreased clonal growth rate, dose-dependent increased formation of cross-linked envelopes, and increased cell planar surface area. Acrolein causes a marked and dose-dependent cellular depletion of total and specific free low-molecular-weight thiols as well as protein thiols. Exposure to acrolein did not cause oxidation of glutathione indicating that thiol depletion occurred by direct conjugation of reduced glutathione to acrolein without concomitant generation of active oxygen species. Furthermore, acrolein is genotoxic and causes both DNA single strand breaks and DNA protein cross-links in human bronchial epithelial cells. The results indicate that acrolein causes several cytopathic effects that relate to multistage carcinogenesis in the human bronchial epithelium.
Grafström
R C
RC
Department of Toxicology, Karolinska Institutet, Stockholm, Sweden.
Dypbukt
J M
JM
Willey
J C
JC
Sundqvist
K
K
Edman
C
C
Atzori
L
L
Harris
C C
CC
D000171:Acrolein / Q000633:toxicity*; D000447:Aldehydes / Q000633:toxicity*; D001980:Bronchi / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage; D004848:Epithelium / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D010960:Plasminogen Activators / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism
D000447:Aldehydes; D013438:Sulfhydryl Compounds; D000171:Acrolein; D010960:Plasminogen Activators