Jd. Hayes et Li. Mclellan, Glutathione and glutathione-dependent enzymes represent a Co-ordinately regulated defence against oxidative stress, FREE RAD RE, 31(4), 1999, pp. 273-300
Increases in the intracellular levels of reactive oxygen species (ROS), fre
quently referred to as oxidative stress, represents a potentially toxic ins
ult which if not counteracted will lead to membrane dysfunction, DNA damage
and inactivation of proteins. Chronic oxidative stress has numerous pathol
ogical consequences including cancer, arthritis and neurodegenerative disea
se. Glutathione-associated metabolism is a major mechanism for cellular pro
tection against agents which generate oxidative stress. It is becoming incr
easingly apparent that the glutathione tripeptide is central to a complex m
ultifaceted detoxification system, where there is substantial inter-depende
nce between separate component members. Glutathione participates in detoxif
ication at several different levels, and may scavenge free radicals, reduce
peroxides or be conjugated with electrophilic compounds. Thus, glutathione
provides the cell with multiple defences not only against ROS but also aga
inst their toxic products. This article discusses how glutathione biosynthe
sis, glutathione peroxidases, glutathione S-transferases and glutathione S-
conjugate efflux pumps function in an integrated fashion to allow cellular
adaption to oxidative stress. Go-ordination of this response is achieved, a
t least in part, through the antioxidant responsive element (ARE) which is
found in the promoters of many of the genes that are inducible by oxidative
and chemical stress. Transcriptional activation through this enhancer appe
ars to be mediated by basic leucine zipper transcription factors such as Nr
f and small Maf proteins. The nature of the intracellular sensor(s) for ROS
and thiol-active chemicals which induce genes through the ARE is described
. Gene activation through the ARE appears to account for the enhanced antio
xidant and detoxification capacity of normal cells effected by many cancer
chemopreventive agents. In certain instances it may also account for acquir
ed resistance of tumours to cancer chemotherapeutic drugs. It is therefore
clear that determining the mechanisms involved in regulation of ARE-driven
gene expression has enormous medical implications.