Biology Reference
In-Depth Information
30
25.0
Liver
Plasma
25
20.0
20
15.0
15
10.0
10
5.0
5
0.0
0
Control
NAC
TAU
TTAU
APAP
NAC +
APAP
TAU +
APAP
TTAU +
APAP
Fig. 20.6
The effects of NAC, TAU, and TTAU on the activities of liver and plasma SOD of rats treated
with a hepatotoxic (800 mg/kg i.p.) dose of APAP. Differences were significant from control at **
p
< 0.01
and ***
p
< 0.001 and from APAP at
†
p
<0.01 and
†††
p
< 0.001. Values are shown as mean ± SEM for
n
= 6
cell susceptibility to APAP toxicity in response to oxidative stress initiated by ROS,
particularly by peroxides normally handled by the GPx/GR system (Adamson and
Harman
1989
). Overdoses of APAP may negatively affect the activity of GPx by
lowering the availability of its cofactor GSH, by promoting the formation of ROS
capable of oxidizing critical thiol groups, and through arylation by NAPQI (Lores
Arnaiz et al.
1995
; Tirmenstein and Nelson
1990
). On the other hand, GR, an enzyme
that converts GSSG back to GSH, may be inhibited by APAP-GSH conjugate (Roušar
et al.
2010
). Not surprisingly, in the present study the activities of GPX and GR were
significantly decreased by APAP in the plasma (−57% and −34%,
p
< 0.01, respec-
tively) and liver (−69%,
p
< 0.001, and −23%,
p
< 0.05, respectively) (Figs.
20.7
and
20.8
). A pretreatment with a sulfur-containing compound ameliorated these losses to
rather similar extents in both the plasma (36-43% for GPx,
p
< 0.01; 3-22% for GR)
and liver (40-52%,
p
£ 0.01, for GPX; £12% for GR).
g-Glutamylcysteine synthetase (g-GCS) catalyzes the rate-limiting step in
de novo synthesis of GSH in liver cells and, consequently, plays a major role in
the antioxidant capacity of these cells. The protective role of this enzyme was
demonstrated by knocking down the heavy chain mRNA of g-GCS in a rat model
to induce a protracted GSH depletion and to potentiate APAP toxicity when com-
pared with normal rats (Akai et al.
2007
). For this reason, individuals who are
heterozygous for g-GCS deficiency may have a limited capacity for detoxifying
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