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which, in turn, causes oxidative stress that may trigger signaling pathways through
mitochondrial toxicity ultimately leading to lethal cell injury.
As stated above, the precise mechanisms by which APAP mediates
hepatotoxicity in both humans and experimental animals still remain to be
elucidated. Metabolic activation of APAP and NAPQI binding to target proteins and
DNA seem to be necessary but are not sufficient for toxicity. Recent findings
indicate that a combination of mitochondrial oxidative stress, increased calcium
levels and other factors may trigger the mitochondrial membrane permeability
transition (MPT) pore opening resulting in the collapse of the transmembrane
potential and then osmotic swelling. These events ultimately cause the rupture of
the outer mitochondrial membrane and release of cytochrome c and other pro-
apoptotic factors into the cytosol (18).
Regarding the signaling pathways mediated by various growth factors and
hormones committed in the regulation of cellular metabolism, differentiation,
growth and survival, protein tyrosine phosphorylation constitutes a key element.
Given the importance of tyrosine kinase signaling in maintaining birth and death
rates of cells, these pathways must be regulated carefully. Protein tyrosine
phosphatases (PTPs) catalyze the dephosphorylation of tyrosine-phosphorylated
proteins (19) and are known to be important negative regulators of growth factor
signaling. Several PTPs have been described which may participate in modulating
the balance between survival and cell death. Among them, protein tyrosine
phosphatase 1B (PTP1B) is a widely expressed non-receptor PTP that is associated
with the endoplasmic reticulum (ER) and other intracellular membranes via a
hydrophobic interaction of its C-terminal targeting sequence (20). In particular,
PTP1B dephosphorylates and inactivates receptors belonging to the tyrosine
kinase superfamily such as the EGF receptor (EGFR) (21), the PDGFR (22), the
insulin receptor (IR) (23) and the IGF-IR (24), all of them implicated in the survival
of hepatocytes (25-26) and many other cellular models. Thus, PTPs represent
novel molecular targets for the development of medicinal reagents that possess
distinct modes of action.
During the last years, our laboratory has been interested in the study of key
proteins that mediate survival pathways in hepatocytes. In this regard, the precise
role of PTP1B in these processes has been investigated in a study published by
Gonzalez-Rodriguez et al. (27) which was performed in immortalized neonatal
hepatocyte cell lines from wild-type (PTP1B
+/+
) and PTP1B-deficient (PTP1B
-/-
)
mice. These cell lines have been proven to be excellent tools for
in vitro
studies of
cell death/survival because they express endogenous pro- and anti-apoptotic
proteins at levels comparable to the liver and hepatocytes of neonatal mice. Using
these cell lines it was demonstrated that the lack of PTP1B protects against
apoptosis induced by trophic factors withdrawal, whereas increased expression of
