Page 279 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

246 SECTION | II Organ Toxicity

VetBooks.ir transporters can be induced or inhibited by drugs that are TYPES OF TOXICANT-INDUCED LIVER
ligands of various nuclear receptors, such as aryl hydro-
INJURY
carbon receptor (AhR), constitutive androstane receptor
(CAR), and pregnane x receptor (PXR). Cell Death
The ABCB1 gene for p-glycprotein is of particular
Necrosis is the predominant form of cell death in most
interest in veterinary medicine because a defect in this
toxic insults. Microscopically visible degenerative
gene caused by a base pair deletion is common in many
changes to the hepatocyte may precede necrosis, includ-
dog breeds (Merola and Eubig, 2014). A deletion muta-
ing ballooning degeneration, hyaline degeneration, and
tion has also been described in cats (Mealey and Burke,
the presence of Mallory bodies (Zimmerman, 1999). Cells
2015). P-glycoprotein is well known as an efflux mecha-
lose osmotic homeostasis and swell, as can be seen on
nism that excludes certain xenobiotics, such as avermec-
light microscopy. Swelling of organelles is seen only on
tins, from the blood-brain barrier, but p-glyoprotein is
an ultrastructural basis (Dahm and Jones, 1996; Treinen-
also involved in transport across canalicular epithelium,
Moslen, 2001). Energy production fails due to loss of cal-
and thus is involved in xenobiotic excretion (Merola and
cium homeostasis (Dahm and Jones, 1996; Zimmerman,
Eubig, 2014).
1999). Eventually there is rupture of cellular membranes
and leakage of cell contents, including cytosolic enzymes
such as alanine transaminase and sorbitol dehydrogenase.
Inflammation Aspartate transaminase is a mitochondrial enzyme that
can also into the circulation from necrotic hepatocytes
Inflammatory reactions represented by activation of
(Chapman and Hostuler, 2013). Depending on the extent
resident Kupffer cells, natural killer cells, and natural
of liver necrosis, overall liver function may or may not be
killer T cells, and migration of activated neutrophils,
affected.
lymphocytes, and monocytes in the damaged areas of
As noted, necrosis is often initiated by damage to
liver parenchyma are commonly seen in toxin-induced
membranes, either the plasma membrane of the cell or the
hepatopathy. Although the main role of this inflamma-
membranes of organelles, particularly the mitochondria,
tory response is to remove dead and damaged cells,
such as with acetoaminophen toxicosis. Cell membrane
it can also aggravate the injury by releasing or
damage can be caused by peroxidation of membrane
forming cytotoxic pro- and antiinflammatory mediators
phospholipids, such as with carbon tetrachloride (CCl 4 ).
(Jaeschke, 2008).
Damage to the plasma membrane interferes with ion regu-
Upon activation, Kupffer cells generate ROS, such
lation; damage to the membranes of the mitochondria
as hydrogen peroxide, by the action of NADPH oxidase.
interferes with calcium homeostasis and energy produc-
These ROS will diffuse into neighboring hepatocytes,
tion; and damage to the smooth endoplasmic reticulum
produce oxidative stress, and lead to cell injury. It has
membrane diminishes the ability of that organelle to
been determined that intracellular proteins, such as
sequester calcium (Zimmerman, 1999). Inhibition of pro-
high-mobility group protein 1 (HMGB-1), released by
tein synthesis is an alternate mechanism of cell necrosis.
cells during necrosis bind to toll-like receptors on
Toxicants that inhibit protein synthesis include amanitin
Kupffer cells, induce synthesis and release of cytokines
and related mushroom toxins, which inhibit the action of
and chemokines (such as TNF-α, IL-1) leading to
RNA polymerase and therefore mRNA synthesis (Pineiro-
recruitment of cytotoxic neutrophils, which can directly
Carrero and Pineiro, 2004).
cause apoptotic cell death or generate ROS, such as
Necrotic liver injury can be focal, zonal, bridging, or
hypochlorus acid, by the actions of NAPDH oxidase
massive and panlobular. Focal necrosis is randomly dis-
and myeloperoxidase, leading to cell injury and death
tributed and involves hepatocytes individually or in
(Jaeschke, 2008).
small clusters (Treinen-Moslen, 2001). Zonal necrosis is
The role of Kupffer cells in toxicant-induced liver injury
common and usually occurs in zone 3, the centrilobular
from variety of chemicals such as ethanol, acetaminophen,
area (Zimmerman, 1999; Treinen-Moslen, 2001;
and 1,2-dichlorobenzene has been studied.
CCl 4
Plumlee, 2004) due to a higher concentration of phase I
Involvement of neutrophils has been shown with hepatotox-
enzymes in this region. Grossly, the liver will have a
icity associated with alpha-naphthylisothiocyanate and halo-
reticulated pattern of dark red central areas separated by
thane. Although many compounds such as ethanol, allyl
brown to yellow areas. Bridging necrosis describes con-
alcohol, aflatoxin B 1 , monocrotaline, ranitidine and diclofe-
fluent areas of necrosis extending between zones of the
nac are capable of causing liver injury without the involve-
lobule or between lobules (Treinen-Moslen, 2001).
ment of neutrophils, inflammatory response initiated by
Panlobular or massive necrosis denotes hepatocyte loss
endotoxin triggers a neutrophil-induced injury or aggravates
throughout the lobule and loss of lobular architecture.
the existing injury.