Biology Reference
In-Depth Information
(continued)
benzene toxicity. Similarly, there are at least two toxic species for AA (AA
itself, N-acetyl-p-benzoquinoneimine), three target sites (hepatocellular
membrane, mitochondria, Kupffer cells), and two types of kinetics (effective
and ineffective), thus giving rise to 2
12 possible mechanisms of
AA toxicity. Such multiple mechanistic possibilities for AA and BZ toxicity
are not surprising in view of the complex living systems with which they
interact
A mechanism of chemical toxicity published in (Ji 1989) that is consistent
with the
Toxicological Uncertainty Principle
described in this section
3
2
ΒΌ
My students and I demonstrated in the isolated perfused rat live system that
acetaminophen and its metabolite, NAPQI, can inhibit mitochondrial respiration
both reversibly and irreversibly (Cheng and Ji 1984; Esterline et al. 1989), poten-
tially weakening various intracellular self-defense mechanisms driven by ATP
(Ji 1987) (see Steps 8, 9, and 10 in Fig.
20.2
).
Using the same experimental system as in Fig.
20.2
and isolated granulocytes
and hepatocytes from the rat, we also demonstrated that the irreversible inhibition
of mitochondrial respiration was
M metyrapone, indicating that NAPI was not generated
from cytochrome P-450.
2. Accompanied by lactate dehydrogenase release.
3. Blocked by 10 mM mannitol, a hydroxyl radical scavenger.
4. Required Ca
++
in the perfusate.
5. Abolished in the liver isolated from hypophysectomized rats.
6. Abolished in the liver isolated from thyroidectomized rats, and
7. Enhanced in the liver isolated from adrenalectomized rats.
In addition we found that
8. Isolated granulocytes (also called neutrophils) caused the covalent binding of
tritiated acetaminophen (
3
H-AA) to granulocyte proteins when stimulated with
phorbol myristate acetate.
9. Synthesized NAPQI irreversibly inhibited the respiration of isolated rat liver
mitochondria, and
10. The acute administration of alcohol to rat increased the liver content of
granulocytes by threefold.
1. Not blocked by 500
m
To account for these varied experimental observations, we were led to propose
the 14-step mechanism for the alcohol-potentiated acetaminophen hepatotoxicity
shown in Fig.
20.3
. In a separate series of experiments performed in collaboration
with D. Laskin and her group at Rutgers, we discovered that acetaminophen
hepatotoxicity is in part mediated by macrophages (Laskin et al. 1986), which
could be readily accommodated by including liver macrophages (also called
