Chemistry Reference
In-Depth Information
reductase, and glutathione peroxidase, were observed
when CRL-1439 normal liver cells were exposed to Cd
(100-300
Cd reduced the amount of HIF-1
α
protein in
hypoxia and inhibited HIF-1
accumulation induced
by Co and desferrioxamine (DFO), although it did not
affect the levels of HIF-1
α
M
) (Ikediobi
et al.
, 2004). In mouse neuronal
cells, Cd induced ROS, which in turn, activated JNK
and p38, as well as their substrates, such as activating
transcription factor 2 (ATF-2), CRE-binding protein
(CREB), and c-Jun. This response was accompanied
by the induction of HO-1, poly (ADP-ribose) polymer-
ase cleavage, and a caspase-independent cell death
( Rockwell
et al.
, 2004).
MAPKs (i.e., ERK, JNK, and p38) are activated
with differing sensitivity to Cd exposure. In CL3
human non-small cell lung carcinoma cells, the
kinase activity of JNK was induced dose depend-
ently by Cd (30-160
µ
mRNA in Hep3B human
hepatoma cells. Antioxidants and a proteasome inhibi-
tor prevented the HIF-1
α
degradation caused by Cd,
indicating that Cd triggered a redox/proteasome-
dependent degradation of HIF-1
α
protein, reducing
HIF-1 activity, and in turn, suppressing the induction
of hypoxia-inducible genes (Chun
et al.
, 2000).
Cd induced signifi cant activation of AP-1 and all
three members of the MAPK family in mouse epider-
mal JB6 cells, and activated ERK was involved in Cd-
induced AP-1 activity (Huang
et al.
, 2001c). Exposure
of mesangial cells to Cd caused an increase of protoon-
cogene
c-fos
mRNA level. Activation of ERK and JNK
acted in concert during the Cd-induced
c-fos
increase
(Ding and Templeton, 2000a; 2000b; Wang and Tem-
pleton, 1998). JNK activity and c-jun mRNA levels, as
well as AP-1 DNA binding activity, were signifi cantly
enhanced by Cd in primary rat hepatocytes (Hsiao and
Stapleton, 2004).
In mouse brain microvessel endothelial cells
(bEnd.3), Cd induced the translocation of NF-
α
µ
M
) treatment. High doses of
Cd (130-160
M
) markedly activated p38, but low Cd
doses did not. Conversely, the activity of ERK was
decreased by doses of Cd (
µ
M
) and moderately
activated by high Cd doses. Low doses of Cd tran-
siently activated JNK and simultaneously reduced
ERK activity, whereas high doses of Cd persistently
activated JNK and p38. JNK and p38 cooperatively
participated in apoptosis induced by Cd. In addition,
the decreased amount of ERK signaling induced by
low Cd doses contributed to growth inhibition or
apoptosis (Chuang
et al.
, 2000). In CCRF-CEM cells, a
human T cell line, ERK and p38 were phosphorylated
by 1
≤
80
µ
B and
increased its DNA binding activity. This activation
was required for Cd-induced intercellular adhesion
molecule-1 (ICAM-1) expression (Jeong
et al.
, 2004).
κ
M
of
Cd were required for the phosphorylation of JNK. In
the time-course study, ERK and p38 were phosphor-
ylated earlier than JNK after Cd exposure (Iryo
et al.
,
2000). It has also been shown that exposure of human
breast cancer cells (MCF-7) to 10
µ
M
of Cd, whereas levels greater than 20
µ
6.3.3 Cr
Chromium (Cr (VI)) can generate ROS, activate
MAPKs, NF-
B, and HIF-1 in cells. Cr mediates free rad-
ical generation by Fenton-type reaction, Haber-Weiss
reaction, or by reacting directly with cellular molecules
(Leonard
et al.
, 2004b). It has been shown that Cr (VI)
was able to enter A549 cells at low concentrations (<10
µ
κ
M
Cd stimulated
phosphorylation of ERK, JNK, and p38, and activa-
tion of p38 pathway was required for Cd-induced
HO-1 gene expression (Alam
et al.
, 2000). Pulse treat-
ment of U-937 monocytic cells with Cd (2 hours at
200
µ
M
), resulting in an elevation of ROS in cells (Liu
et al.
,
2001a). In the same cell line, Cr-induced ROS generation
was shown to be responsible for the early stage of Cr-
induced apoptosis, whereas Cr-activated p53, mostly
by ROS-mediated free radical reactions, contributed
to a late stage induction of apoptosis (Wang and Shi,
2001; Ye
et al.
, 1999). Cr (VI)-induced ROS production,
as well as oxidative damage to tissue and to DNA, was
also observed in a number of cell lines, such as human
peripheral blood mononuclear cells, chronic myelog-
enous leukemic K562 cells, and J774A.1 murine mac-
rophage cells. Moreover, p53 has been shown to play a
major role in Cr (VI)-induced oxidative stress and toxic-
ity (Bagchi
et al.
, 2001). ROS acted as a second messenger
mediating Cr (III)-induced apoptosis in lymphocytes. It
activated the Src-family tyrosine kinases, which, in turn,
led to the activation of caspase-3 in Cr-induced apoptotic
cell death (Balamurugan
et al.
, 2002; 2004).
M
) induced a rapid phosphorylation of p38, as
well as a late phosphorylation of ERK. P38 activation
was an early and specifi c regulatory event for the
Cd-induced apoptosis (Galan
et al.
, 2000). Cd persist-
ently activated the JNK pathway in LLC-PK1, a renal
epithelial cell line, and an elevation of intracellular
Ca was required for this activation (Matsuoka and
Igisu, 1998). P38 and ERK can be simultaneously or
independently activated, depending on the concen-
trations of Cd ranging from 40-100
µ
M
. These signal-
ing pathways have been shown to participate in the
induction of heat shock proteins (HSPs) by Cd in 9L
rat brain tumor cells (Hung
et al.
, 1998).
Cd has been shown to increase p53 protein level and
induce phosphorylation of p53 at Ser 15 in MCF-7 cells,
and this effect depends on PI3K related kinases, but
not on MAPKs (Igisu, 2001).
µ
