Protein tyrosine phosphatase deficiency…
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1. INTRODUCTION
Acetaminophen
(APAP) or Paracetamol is a widely used analgesic and
antipyretic drug safe at therapeutic doses (1). However, an accidental or
intentional overdose can induce severe hepatotoxicity in both experimental
animals and humans (2). The first reports of APAP hepatotoxicity in humans
appeared in the literature in the 1960s. In fact, APAP overdose is the most frequent
cause of drug-induced liver failure in the United States and in Great Britain at
present (3). Therefore, APAP-induced acute toxicity has become an essential model
for studying drug-induced liver and kidney failure. In the liver, APAP overdose
produces a centrilobular hepatic necrosis that can be fatal and is increasingly
recognized as a significant public health problem (4-6). Moreover, APAP overdose
is also the second leading cause of liver transplantation, which accounts for
considerable levels of morbidity and mortality (7).
APAP is commonly used for the relief of minor pains like headaches and in
combination with opioid analgesics is also used in the management of more severe
pains in advanced cancer and in post-operative periods. While APAP has analgesic
and antipyretic properties comparable to those of aspirin, its anti-inflamatory
effects are weak. The mechanisms underlying APAP-induced liver injury have been
studied for several decades and excellent recent reviews have revealed the main
cellular and molecular pathways involved in its toxic response (8-12). However,
despite of substantial progress in our understanding of APAP-induced
hepatotoxicity, additional mechanisms responsible of the cellular damage induced
by this drug remain still unknown.
The initial step in APAP-mediated toxicity is initiated by cytochrome P-450
(CYP) by a direct two electron oxidation of APAP, a previously unrecognized
mechanism of CYP P450-mediated reactions, that convert APAP to the reactive
metabolite N-acetyl-p-benzoquinone imine (NAPQI) causing glutathione (GSH)
depletion and covalent binding to hepatic parenchymal cell proteins and DNA (13).
The CYP isoforms important in APAP metabolism are CYP2E1, CYP1A2, CYP3A4
and CYP2D6 (14-15). Moreover, generation of reactive oxygen (ROS) and nitrogen
species, lipid peroxidation, mitochondrial dysfunction, disruption of calcium
homeostasis and induction of apoptosis and necrosis are also involved in APAP-
induced hepatotoxicity (16).
At therapeutic doses, NAPQI is efficiently detoxified by GSH and eliminated
in the urine or bile as APAP–cysteine, APAP–N-acetylcysteine (APAP–NAC), and
APAP–glutathione (APAP–GSH). After an overdose of APAP, the glucuronidation
and sulfation routes become saturated and more extensive bioactivation of the
drug occurs leading to rapid depletion of the hepatic GSH pool. Subsequently,
NAPQI binds to cysteine groups on cellular proteins forming APAP-protein adducts
(17). Of note, NAPQI also binds to a number of mitochondrial proteins (9-10)
