Page 275 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

242 SECTION | II Organ Toxicity

VetBooks.ir sinusoidal membrane. Lysosomes within hepatocytes are the blood in zone 1, and there is little uptake by the time
blood reaches zone 3.
involved in storage and export of metals and minerals
Bile secretion is a major hepatic function and essen-
into canaliculi.
Sinusoids are located between cords of hepatocytes, tial for uptake of lipid nutrients, protection against oxi-
which are larger than capillaries and lined by special- dative insults in the small intestine, and for excretion of
ized endothelium. The endothelial lining is discontinu- endogenous and xenobiotic compounds. Bile is com-
ous, the sinusoidal endothelial cells having fenestrae, to posed of bile salts, bilirubin, GSH, phospholipids, cho-
allow movement of fluid and molecules less than lesterol, proteins, organic anions, metals and conjugated
259 kDa into the space of Disse, located between the xenobiotics (Treinen-Moslen, 2001; Pineiro-Carrero and
endothelium and the hepatocytes (Watkins, 1999; Pineiro, 2004).
Treinen-Moslen, 2001; Plumlee, 2004). Within the Canaliculi enter canals of Hering in the portal triad
space of Disse, hepatocytes contact free and protein that leads to interlobular and intrahepatic bile ducts, sur-
bound molecules that may be absorbed by diffusion or rounded by bile duct epithelial cells, which coalesce to
aforementioned active transport (Watkins, 1999). form the hepatic bile duct. Most animal species have a
Remarkable metabolic diversity of the hepatic zones is gall bladder for bile storage but it is absent in others:
needed in order to accommodate the liver’s numerous horses and related species, rhinoceroses and tapirs, ele-
functions. Zone 3 hepatocytes are involved in glycolysis phants, camelids, porcupines, pigeons, rats, deer, ratites,
and lipogenesis. Zone 1 hepatocytes are involved in bile and many parrots. Gall bladders may or may not be pres-
salt extraction, fatty acid oxidation, gluconeogenesis ent in giraffes and hippopotamuses (Oldham-Ott and
and protein synthesis and thus are rich in mitochondria Gilloteaux, 1997). Most carnivores have a gall bladder,
for energy production (Treinen-Moslen, 2001; Pineiro- the exceptions being dolphins and other cetaceans.
Carrero and Pineiro, 2004; Plumlee, 2004). Gradients of The gall bladder stores and concentrates bile, then
metabolic enzymes involved in bioactivation and detoxi- empties into the duodenum. When the gall bladder is
fication have been shown along different zones of the absent, bile empties directly into the duodenum
acinus (reviewed by Jungermann and Katz, 1989). Zone (Ramaiah, 2007). Bile enhances nutrient uptake in the
3 is particularly rich in phase I metabolic enzymes and small intestine, protects enterocytes from oxidation and
zone 1 has the highest concentration of GSH involved in facilitates excretion of xenobiotics and endogenous waste
phase II metabolism (Thawley, 2016). in the feces (Treinen-Moslen, 2001).
The blood supply of the liver is mainly from the portal
vasculature: 60% 80% from branches of the portal vein, Cell Types of the Liver
which is oxygen depleted but supplies nutrients, xenobio-
tics, and toxicants from the GIT, and 20% 40% from the Seven intrinsic cell types have been identified in the liver:
hepatic artery, which is oxygenated (Treinen-Moslen, the parenchymal cells (or hepatocytes), the hepatocytic
2001). Oxygen is quickly consumed to meet the high met- stem cells (oval cells) and five nonparenchymal cell
abolic demands of the parenchymal cells as the blood types. Nonparenchymal cells include bile duct epithelium,
flows towards the terminal hepatic venule, also known as sinusoidal endothelium, described above, as well as resi-
central vein. As a consequent of this structure, hepato- dent macrophages (Kupffer cells), large granular lympho-
cytes in zone 1 receive blood that is 9% 13% oxygenated cytes (pit cells), and lipid storing hepatic stellate cells
but nutrient replete, whereas blood received by zone 3 is (HSC or Ito cells). Hepatocytes represent about 60% of
only 4% 5% oxygenated and nutrient depleted (Sturgill the total cell number and 80% of hepatic tissue volume in
and Lambert, 1997; Treinen-Moslen, 2001). Therefore the rat liver, and the smaller nonparenchymal cells are
zone 3 or the centrilobular zone is susceptible to hypoxia estimated to constitute about 30% of total cellular popula-
(Thawley, 2016). tion, but only 6% 7% of tissue volume (Dahm and
Another well-known gradient seen in acinar zonation Jones, 1996).
is that of bile. Bile salts and bilirubin from blood enter Oval cells, the hepatocytic stem cells, are located in
hepatocytes via active transporters on the sinusoidal mem- the canals of Hering, where bile canaliculi from the
brane, then are secreted into canalicular lumen via the hepatic cords converge with bile ductules of the portal
canalicular membrane (Treinen-Moslen, 2001). Bile cana- triad. If hepatocyte replication is impaired, the oval cells
liculi are dynamic structures formed between hepatocytes proliferate and differentiate and eventually become both
by the hepatocyte membranes (Treinen-Moslen, 2001; hepatocytes and biliary epithelial cells (Fausto and
Plumlee, 2004). Bile flows from hepatocytes into canali- Campbell, 2003; Jaeschke, 2008). Experimental blockade
culi, and towards the bile duct within the portal triad of of hepatocyte proliferation can potentially lead to contin-
the acinus, from zone 3 to 1, in the opposite direction of ued oval cell proliferation, leading to neoplastic transfor-
the blood flow. Bile salts are efficiently extracted from mation and resulting in hepatocellular tumors.