Biology Reference
In-Depth Information
calculate the Kosko entropies for all the
competing statements
about how acetamin-
ophen injures the liver in order to evaluate the degree of certainty of their claims.
To accomplish this task, it is necessary to summarize relevant existing knowledge in
the form of various mechanistic schemes or pathways, two of which are discussed
below.
In the early 1980s when I first entered the field of toxicology, one of the most
intensely studied toxicant was acetaminopen. Although, when taken in pharmaco-
logical doses, acetaminophen is safe, it can injure the liver when taken in toxicolog-
ical (or suicidal) doses (Black 1984). Many toxicologists believed in the hypothesis
that the mechanism of the toxic action of this drug involved following key steps:
1. Themetabolic activation of acetaminophen into its reactive intermediate catalyzed
by cytochromes P-450 and other pro-oxidant enzymes (Kocsis et al. 1986), later
found to be N-acetyl-p-benzoquinone imine (NAPQI) (Dahlin et al. 1984),
2. The depletion of the intracellular antioxidant, glutathione, GSH, and
3. The covalent-binding of NAPQI to essential nucleophiles including proteins
and DNA when the GSH store is depleted below a critical level (James et al.
2003).
Because of the highly reactive nature of NAPQI, it can bind nondiscriminately to
all electron-rich atoms, making it difficult to pinpoint the critical macromolecule
leading to cell injury. The experimental data available in the late 1980s indicated to
me that the molecular mechanisms underlying acetaminophen hepatotoxicity may
not be as simple (i.e., certain) as then widely believed, prompting me to propose
what I called the “multiple metabolite-multiple target” (MMMT) hypothesis of
chemical toxicity reproduced below:
The Toxicologist 9(1):161 (1989)
“MULTIPLE METABOLITE-MULTIPLE TARGET” HYPOTHESIS AS
APPLIED TO BENZENE AND ACETAMINOPHEN TOXICITY.
S. Ji, Dept. of Pharmacol. and Toxicology, Rutgers University, Piscataway, N.J.
Existing experimental data on benzene (BZ) and acetaminophen (AA) toxic-
ity support the general concept that the toxicological consequences of these
compounds are derived not from one but many reactive or stable molecular
species related to them and that these toxic species interact with not one but
multiple molecular targets (“toxicological receptors”). In addition, the kinet-
ics of the interactions between toxic metabolites and their respective targets is
critical in the expression of the toxic potential of these xenobiotics. There are
at least six possible toxic benzene metabolites (phenol, hydroquinone, p-
benzoquinone, catechol, trihydroxybenzene and muconaldehyde), two target
cell groups in bone marrow (stroma and stem cell), and two kinds of kinetics
(one fast enough to effectuate toxic manifestations and the other too slow to
do so), so that there are at least 6
2
2
24 possible mechanisms for
¼
(continued)
