Page 285 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

252 SECTION | II Organ Toxicity

VetBooks.ir people. Alcoholic steatosis and other forms of hepatic (intrahepatic) or outside the liver (extrahepatic). Causes
of cholestasis include hepatobiliary tumors, endotoxemia,
steatosis have been linked to impairment of ATP homeo-
hepatocyte swelling and intraductal crystals such as cal-
stasis and mitochondrial abnormalities have been reported
in a growing body of literature. Aspirin, valproic acid, cium salts of plant saponins, e.g., those found in Tribulus
and tetracyclines inhibit beta oxidation of fatty acids in spp. Most chemicals that cause cholestasis are excreted in
mitochondria leading to lipid accumulation. the bile, including the mycotoxin sporidesmin, which con-
centrates 100-fold in the bile (Treinen-Moslen, 2001).
Disruption of the hepatocyte cytoskeleton produces
Disruption of Cytoskeleton
cholestasis by preventing the normal pulsatile contractions
Changes in intracellular calcium homeostasis produced by that move bile through the canalicular system to the bile
active metabolites of xenobiotics can disrupt the dynamic ducts. Drugs that bind to actin filaments, such as phalloi-
cytoskeleton. A few toxicants cause disruption of the din, those that affect cytoskeletal assembly, such as
cytoskeleton through mechanisms independent of bio- microcystin, and those that affect calcium homeostasis
transformation. Microcystin is one example. Microcystin and cellular energy production can generate this type of
is produced by the cyanobacterium M. aeruginosa and injury. Cholestatic disorders typically result in elevated
other species of cyanobacteria. The hepatocyte is the spe- serum alkaline phosphatase, gamma-glutamyltransferase
cific target of microcystin, which enters the cell through a and serum bilirubin.
bile-acid transporter. Microcystin covalently binds to ser- Cholangiodestructive cholestasis is caused by intrahe-
ine/threonine protein phosphatase, leading to the hyper- patic or extrahepatic bile duct obstruction. Injury of bili-
phosphorylation of cytoskeletal proteins, and deformation ary epithelium leads to cell edema, sloughing into the
and loss of function of the cytoskeleton (Treinen-Moslen, lumen, and inflammation, contributing to obstruction
2001). (Treinen-Moslen, 2001; Plumlee, 2004). Chronic lesions
Phalloidin and related toxins found in some mush- of cholangiodestructive cholestasis typically include bile
rooms, including A. phalloides, act by binding tightly to duct proliferation and periductular fibrosis. Vanishing bile
actin filaments and preventing cytoskeletal disassembly, duct syndrome, characterized by a loss of bile ducts, has
again causing deformation and loss of cytoskeletal func- been described in chronic cholestatic disease in humans
tion (Treinen-Moslen, 2001). (Zimmerman, 1999; Treinen-Moslen, 2001) and produced
experimentally in dogs (Uchida et al., 1989).
Cholestasis
Hepatogenous Photosensitization
Cholestasis can be transient or chronic (Treinen-Moslen,
2001). If severe, bile pigments make the liver appear Cholestatic diseases in herbivores, ruminants in particular,
grossly yellow to yellow-green (Plumlee, 2004). Cholestasis are associated with dermal photosensitization. The presen-
is subdivided into canalicular cholestasis and cholangiodes- tation of photosensitization is similar to that of sunburn,
tructive cholestasis. but with a more rapid onset and associated with different
Canalicular cholestasis can be produced by drugs/che- wavelengths of light (Rowe, 1989). Photosensitization
micals that damage the structure and function of bile is caused by circulation of photoactive compounds.
canaliculi. A key component of bile secretion involves Primary photosensitization involves ingestion or dermal
several ATP-dependent export pumps, such as the canalic- absorption of a photodynamic compound that enters
ular bile salt transporter and other transporters that export the circulation, such as hypericin from Hypericum perfor-
bile constituents from the hepatocyte cytoplasm to the atum or St. John’s wort, and is described elsewhere. The
lumen of the canaliculus. Some drugs bind these trans- second type of photosensitization is hepatogenous
porter molecules, arresting bile formation and movement photosensitization.
within the canalicular lumen (Klaassen and Slitt, 2005). Hepatogenous photosensitization usually occurs sec-
Secondary bile injury results if there is cholestasis due to ondary to cholestasis. Herbivores ingest large quantities
the detergent action of bile salts on the biliary epithelium of chlorophyll. Metabolism of chlorophyll by bacteria in
or hepatocytes in areas of cholestasis. Enzymes associated the GIT produces phylloerythrin, a photoactive compound
with the bile duct canaliculus include aldehyde dehydro- that is absorbed and is predominantly excreted in the bile
genase and gamma-glutamyltransferase, which can leak (Rowe, 1989; Burrows and Tyrl, 2001). Cholestasis pre-
into the circulation during bile stasis or damage to the vents excretion of this compound and, upon exposure to
biliary epithelium, as can bile acids (Chapman and light of wavelengths 320 400 nm, circulating phylloery-
Hostutler, 2013). thrin contributes to generation of singlet oxygen, causing
Cholestasis can also occur simply from physical lipid peroxidation in areas of skin unprotected by hair or
obstruction of canaliculi within the liver parenchyma melanin (Burrows and Tyrl, 2001). Not all causes of