Carcinogenesis, Vol 19, 797-801, Copyright © 1998 by Oxford University Press
T Muller and S Gebel
Mainstream cigarette smoke (CS) trapped in phosphate-buffered saline
solutions (smoke-bubbled PBS) has been shown to induce a strong stress
response in cultured cells. This is reflected, for example, by the
expression of stress genes such as c-fos and haem oxygenase, a transient
decrease in the translation efficiency and the induction of cell cycle
arrest. In these studies, peroxynitrite, the reaction product of nitric
oxide (NO) and superoxide (O2-.), was identified as an active principle
formed by CS in aqueous solutions. In the present study, we show that the
CS-induced stress response is critically dependent on the intracellular
glutathione (GSH) content which itself becomes diminished in cells exposed
to smoke-bubbled PBS. Investigations using c-fos expression as a measure
for cellular stress revealed a direct correlation between the smoke-bubbled
PBS concentration necessary for stress-dependent c-fos expression and the
intracellular GSH concentration observed in different cell lines.
Correspondingly, 3T3 fibroblasts artificially depleted of GSH by
pretreatment with buthionine-sulphoximine (BSO), an inhibitor of GSH
synthesis, require significantly lower amounts of smoke-bubbled PBS to
obtain a detectable c-fos expression, whereas, supplementation of the
medium with N-acetyl-cysteine is an efficient treatment for the inhibition
of a CS-induced c-fos response. We also show that the smoke- bubbled
PBS-dependent loss of intracellular GSH is mainly attributable to the
aldehyde fraction of CS, although these aldehydes by themselves cannot
induce c-fos in these cells. The smoke-bubbled PBS-dependent c- fos
response can, however, be mimicked when peroxynitrite and CS- related
aldehydes, at the concentrations calculated to appear in smoke- bubbled
PBS, are used in combination for cell exposure. Taken together, these
results suggest that in cells exposed to aqueous extracts of CS,
smoke-related aldehydes decrease the intracellular GSH content
significantly, allowing peroxynitrite to interfere with specific target
molecules resulting in the stress-specific expression of c-fos.
ARTICLES
The cellular stress response induced by aqueous extracts of cigarette smoke is critically dependent on the intracellular glutathione concentration
INBIFO Institut fur biologische Forschung, Koln, Germany. th.w.mueller@t-online.de
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