active metabolic intermediates such as A-acetyl benzoquinoneimine. The for-
mation of glutathione is summarized in Figure 40-4. y-Glutamylcysteine syn-
thetase catalyzes the formation of the dipeptide y-glutamylcysteine from the
amino acids glutamate and cysteine using energy provided by the hydrolysis
of ATP to ADP and phosphate. Glutathione synthetase catalyzes the addition
of glycine to y-glutamylcysteine to form the tripeptide glutathione, again using
1 mol of ATP.
The role of the glutathione in detoxifying A-acetyl benzoquinoneimine is
shown in Figure 40-3. The adduct acetaminophen glutathionate is no longer
toxic to cells and can be excreted without further damage. Any process
depleting glutathione levels would compromise the ability of the cell to
protect itself against A-acetyl benzoquinoneimine. This includes deficien-
cies of any of the enzymes involved in the synthesis of glutathione or that keep
glutathione in its reduced state as well as any other radical generating process
that consumes glutathione. In the case of acetaminophen overdose, in addition
to giving activated charcoal to absorb excess stomach and intestinal acetamin-
ophen or its conjugates, a strategy to replenish glutathione concentration is
important. The most frequently administered compound is A-acetylcysteine.
Easily obtainable and readily soluble, it serves to facilitate glutathione syn-
thesis by increasing the concentrations of one of the reactants of the first
synthetic step. The committed dipeptide product being made, glutathione is
synthesized to replenish depleted supplies. A-acetylcysteine seems most effec-
tive when given less than 10 hours after ingestion of acetaminophen but is rec-
ommended within the first 35 hours after ingestion.
X - C - C H
- C - N - C - C - N - C H
- C '
Figure 40-4. Glutathione formation.