Page 276 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Liver Toxicity Chapter | 15 243

VetBooks.ir New hepatocytes from zone 1 progress down hepatic (MDR) proteins. Polymorphisms in these proteins have
been associated with increased susceptibility to certain
cords to replace the aging zone 3 hepatocytes.
Kupffer cells represent 80% of the fixed macrophages
xenobiotics (Shehu et al., 2016). Other xenobiotics can
in the body (Treinen-Moslen, 2001). These macrophages affect the activity of MDR and canalicular transport
are usually located within sinusoids and are closely asso- proteins.
ciated with endothelial cells, though they can migrate to Liver cells can accumulate high concentrations of
areas of injury (Thawley, 2016). Kupffer cells are phago- metals and vitamins, leading to injury. For example,
cytes, ingesting foreign material from the portal circula- excessive storage of vitamin A in stellate cells produces
tion (Treinen-Moslen, 2001; Plumlee, 2004; Thawley, engorgement, activation, and proliferation of these cells
2016), debris from apoptotic or necrotic hepatocytes, and (Treinen-Moslen, 2001). Chronic high vitamin E concen-
microbes and microbial antigens (Thawley, 2016). trations produce hepatic fibrosis and portal hypertension
Kupffer cells act as antigen presenting cells and secrete in humans, precipitating continued fibrosis (Zimmerman,
various cytokines (Treinen-Moslen, 2001; Plumlee, 2004), 1999; Pineiro-Carrero and Pineiro, 2004; Maddrey, 2005).
and are involved in destruction of metastatic neoplastic Cadmium is sequestered by hepatic metallothioneins but
cells (Plumlee, 2004). Kupffer cells may store minerals produces pathology when storage capacity is exceeded.
and are involved in the pathogenesis of a variety of liver The liver is also responsible for iron homeostasis. Iron
diseases induced by toxicants such as ethanol (Laskin, uptake from the sinusoids is receptor mediated and
1990; Thurman, 1998). sequestration occurs through binding with iron storage
Pit cells are natural killer cells with antineoplastic proteins such as ferritin. High hepatic iron concentrations
functions, are involved in granuloma formation, and produce lipid peroxidation affecting zone 1 hepatocytes
reside within sinusoids (Treinen-Moslen, 2001; Plumlee, (Treinen-Moslen, 2001). Certain mammals, including
2004). Pit cells can proliferate locally when stimulated to Egyptian fruit bats, and some fruit-eating bird species
attack tumor cells together with Kupffer cells (Wisse including mynahs, toucans, aracari, and birds of paradise,
et al., 1997). tend to have hemosiderosis (accumulation of iron in the
HSCs or Ito cells are located in space of Disse and liver) and are prone to hemochromatosis (disease associ-
store fat and vitamin A (Treinen-Moslen, 2001; Pineiro- ated with iron sequestration). Increased expression of iron
Carrero and Pineiro, 2004; Plumlee, 2004). When there is transporters DMT1 and Ireg1 has been found in mynahs,
liver injury, HSCs are activated to myofibroblast-like and likely causes iron accumulation in this particular spe-
cells (Plumlee, 2004; Maddrey, 2005). Activated stellate cies (Mete et al., 2005). However, the genetic cause(s) of
cells produce collagen and play a role in hepatic fibrosis hemosiderosis have not been completely determined yet.
(Treinen-Moslen, 2001; Plumlee, 2004). The liver also plays an important role in copper
homeostasis and is the most important organ in the body
for copper homeostasis and storage (Dirksen and Fieten,
FACTORS INFLUENCING TOXIC LIVER 2017). Inability to export copper into bile is the cause of
INJURY Wilson’s disease in humans. This disease is caused by a
defect or lack of an autosomal recessive gene called
Uptake and Concentration of Xenobiotics
P-type ATPase (ATP7B), a copper transporter (Jaeschke,
The liver has a dual blood supply as noted above. The 2008). Treatment involves life-long chelation therapy
hepatic artery brings blood from the systemic circulation (Dirksen and Fieten, 2017). Copper storage disease of vet-
and the portal system brings blood directly from the gas- erinary relevance, either mediating or as a result of
trointestinal system. The portal system is involved in the chronic liver damage, is noted in certain breeds of dogs:
“first pass effect,” meaning that nutrients and xenobiotics Anatolian shepherds, Bedlington terriers, Cardigan Welsh
absorbed by the digestive system are filtered through the corgies, clumber spaniels, cocker spaniels, Dalmatians,
liver before entering the systemic circulation (Treinen- Doberman pinschers, Labrador retrievers, Pembroke
Moslen, 2001). Welsh corgies, poodles, Skye terriers, West Highland
The space of Disse allows close contact between cir- white terriers, and others (Rolfe and Twedt, 1995; Spee
culating plasma, plasma proteins, and hepatocytes, allow- et al., 2006; Dirksen and Fieten, 2017). Copper storage
ing rapid diffusion of lipophilic compounds across the disease in Labrador retrievers has been linked to the
hepatocyte membrane (Treinen-Moslen, 2001). Some ATP7B gene, like Wilson’s disease (Dirksen and Fieten,
compounds are specifically taken up by sinusoidal trans- 2017). Deletion of exon 2 of the MURR1 (COMMD1)
porters, including bile acids, phalloidin from several gene, important in regulation of biliary copper excretion,
Amanita spp. of mushrooms, and microcystin produced was found to be the genetic defect in Bedlington terriers
by the cyanobacteria Microcystis aeruginosa. Canalicular (Klomp et al., 2003). Molecular causes in other suscepti-
transporters include multidrug resistance-associated ble breeds remain to be confirmed. Similar to dogs,