react with cellular macromolecules damaging them and the integrity of the
cells wherein the metabolic alteration occurs. The tissue with the highest con-
centration of cytochromes P450 is the liver, and it is there (along with kid-
ney) that acetaminophen causes the most damage. In the liver, N-acetyl
benzoquinoneimine can form arylated derivatives of protein, lipid, RNA,
and DNA, causing destruction of these compounds as well as any larger
structure with which they are associated, for example, cellular and subcellular
membranes, leading to hepatocyte lysis and loss of cellular contents, such as
enzymes, to the circulation. However, N-acetyl benzoquinoneimine may also
disrupt Ca2+ balance, leading to dramatically increased intracellular Ca2+ con-
centrations, that is, 20 |J.M versus 0.1 |J.M, which is the normal concentration.
Ca2+ is a potent and therefore well-regulated signal. Thus dramatic increases in
Ca2+ concentration would have deleterious effects on the balance of many cel-
lular processes, especially energy generation. The low serum calcium and ele-
vated liver enzyme serum levels seen in the patient reflect hepatocyte lysis.
What mechanisms protect against this metabolite-induced destruction of cel-
lular integrity? The primary defense against radical metabolite intermediate-
mediated damage is the glutathione (GSH) system. Glutathione is a tripeptide
with an active sulfhydryl group that plays a role in protection of cellular
macromolecules from attack by radicals such as organic hydroperoxides or
previous page 384 Case Files   Biochemistry read online next page 386 Case Files   Biochemistry read online Home Toggle text on/off