Comparative Evaluation of the Effects of Taurine and Thiotaurine on Alterations of the Cellular Redox Status and Activities of Antioxidant and Glutathione-Related Enzymes by Acetaminophen in the Rat - Advances in Experimental Medicine and Biology - page 187

hepatic stores of glutathione. As a result, NAPQI is left unopposed to effect cell
injury by covalently binding to hepatic proteins, primarily though not exclusively,
to cysteine residues to generate stable 3-(cystein-S-yl) APAP adducts (Nelson and
Bruschi 2003 ). While this mechanism may account for APAP-related cell injury, the
fraction of the dose of APAP entering into covalent binding to hepatic proteins is
small. Hence, additional mechanisms have been postulated to account for the bulk
of liver injury by APAP. One such proposal considers lipid peroxidation (LPO) as a
mechanism of cell death based on the increased formation of reactive oxygen (ROS)
and nitrogen (RNS) species observed in hepatocytes undergoing necrotic changes
(Hinson et al. 2010 ). In this case, the binding of NAPQI to mitochondrial proteins
of the respiratory chain will decrease mitochondrial respiration, oxidative phospho-
rylation, and ATP formation, and the flow of electrons will be diverted towards
oxygen to generate superoxide anion (Jaeschke et al. 2003 ) . In turn, superoxide
anion arising from mitochondrial stress will propagate and amplify the liver injury
upon reacting with nitric oxide to form peroxynitrite, a powerful oxidant and nitrat-
ing agent with the ability to modify cellular macromolecules and to aggravate mito-
chondrial dysfunction and ATP depletion (Jaeschke et al. 2003 ) . Furthermore,
mitochondria oxidative stress will alter calcium homeostasis and calcium-controlled
cellular processes and will stimulate signaling pathways for the activation of trans-
duction responses ending in mitochondrial permeability transition and the loss of
membrane potential, events that further contribute to centrilobular hepatic necrosis
and acute liver failure (Hinson et al. 2010 ) .
In parallel with its depleting action of the intrahepatic glutathione, APAP is
also capable of exerting varying effects on the levels of glutathione disulfide and of
lowering the activities of antioxidant enzymes (catalase, glutathione peroxidase,
superoxide dismutase) as well as of enzymes participating in glutathione redox
cycling (glutathione reductase), utilization (glutathione S-transferase), and synthe-
sis ( g-glutamylcysteine synthetase) (Acharya and Lau-Cam 2010 ) .
In general, the treatment of APAP poisoning has been directed at inhibiting its
activation by the cytochrome P450 enzyme system or at restoring hepatic glutathi-
one reserves to sustain conjugation with glutathione. Since protection of the liver
against APAP toxicity by decreasing the formation of NAPQI through inhibition of
the cytochrome P450 enzyme system with cysteamine, the descarboxy analog of
L-cysteine, was not high enough (Miller and Jollow 1986 ) , most antidotal approaches
for APAP poisoning have been targeted at restoring the levels of intracellular gluta-
thione. In spite of the numerous attempts to develop prodrugs of L-cysteine for GSH
synthesis, only N -acetylcysteine (NAC) has received recognition as a first-line treat-
ment for APAP poisoning. In addition to reversing APAP-induced depletion of glu-
tathione and insuring the excretion of both APAP and NAPQ in the bile as glutathione
conjugates (Lauterburg et al. 1983 ), NAC is also an effective antioxidant (Cotter
et al. 2007 ; Ozaras et al. 2003 ; Sathish et al. 2011 ; Victor et al. 2003 ) .
In a previous study we compared the effects of NAC with those of the sulfonic
(-SO 3 H) and sul fi nic (-SO 2 H) analogs of 2-aminoethane, namely, taurine (TAU) and
hypotaurine (HYTAU), as protection against APAP-mediated LPO, changes in
glutathione redox state, and declines in the activities of enzymes involved in