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Glutathione Articles - Acetaminophen Toxicity
Effect of
Acetaminophen Administration Glutathione Compartmentation Energy
Metabolism in the Rat
Vendemiale G, Grattagliano I, Altomare E, Turturro N and Guerrieri F
Biochem Pharmacol. 1996 Oct 25;52(8):1147-54.
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ABSTRACT
Changes in cell energy
metabolism and mitochondrial dysfunction have been observed after
acetaminophen administration. Because consumption of hepatic glutathione
is closely related to acetaminophen toxicity, we investigated the kinetics
of: 1. glutathione depletion in liver mitochondria and cytosol; 2. State 3
and 4 respiratory rates of succinate-supplemented mitochondria; 3. rate of
ATP synthesis; 4. oligomycin-sensitive ATP hydrolase activity and passive
proton conductivity of inside-out vesicles of the inner mitochondrial
membrane; and 5. changes in hepatic and mitochondrial malondialdehyde in
the rat after in vivo acetaminophen administration. Two hours after
acetaminophen injection, hepatic glutathione decreased and malondialdehyde
increased. In the same interval, an increase in both State 3 and 4
respiratory rates of succinate-supplemented mitochondria was observed.
This was accompanied by a decrease in the rate of ATP synthesis and the
P/O ratio and by an increase in the passive proton permeability of the
inner mitochondrial membrane, which was insensitive to oligomycin. No
significant change in oligomycin-sensitive ATP hydrolase activity was
observed. Four hours after APAP injection, the respiratory rates, as well
as the proton conductivity, decreased, the
rate of ATP synthesis was restored, and the mitochondrial glutathione
started to increase; the cytosolic levels of glutathione were still low
and the cytosolic and mitochondrial levels of malondialdehyde remained
high for 2 more hr. The concentrations of these indices were completely
restored 24 hr postdosing. Our findings suggest that acetaminophen
administration selectively depletes (within 2 hr) mitochondrial
glutathione, and produces local toxicity by altering membrane permeability
and decreasing the efficiency of oxidative phosphorylation. This renders
mitochondria more susceptible to oxidative damage, especially during
increased free radical production, as in the case of enhanced
mitochondrial respiration in State 4. The concomitant restoration of
mitochondrial respiration, oxidative phosphorylation, membrane
permeability, and glutathione levels is consistent with the importance of
the mitochondrial glutathione pool for the protection of the mitochondria
l membrane against oxidative damage.
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