Page 286 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Liver Toxicity Chapter | 15 253

VetBooks.ir cholestasis produce photosensitization, and icterus can P450 enzyme CYP2E1. Studies suggest that thioacetami-
desulfoxide, a relatively stable intermediate of thioaceta-
occur in the absence of photosensitization (Rowe, 1989).
Hepatocyte swelling can produce cholestasis. Agents
mide metabolism, is obligatory for the hepatotoxic effects,
that cause photosensitization through hepatocyte damage indicating that it is the penultimate reactive metabolite.
include the toxic plant Lantana camera that causes Accordingly, it has been reported that the hepatotoxic
steatosis. Plants containing pyrrolizidine alkaloids (such as effects of thioacetamide are only expressed after metabolic
Senecio spp., Crotalaria spp., Cynoglossum spp., conversion to thioacetamide S-oxide, which undergoes fur-
Tetradymia spp., Trifolium hybridum, Artemisia nigra)also ther metabolism to an as yet unidentified metabolite, most
cause secondary photosensitization due to portal fibrosis. likely the reactive unstable thioacetamidesulfone. The reac-
Because significant hepatocyte damage must occur before tive metabolite of thioacetamide binds to liver proteins
the individual presents with photosensitization, damage of with the formation of acetylimidolysine derivatives that are
this type usually carries a poor prognosis (Rowe, 1989). responsible for thioacetamide-induced hepatotoxic effects.
Other agents that damage bile ducts include the myco- Progression of thioacetamide-induced liver injury has also
toxin sporidesmin and sapongenins from the plant Tribulus been attributed to inhibition of the tissue repair response in
terrestris. Sporidesmin is produced by Pithomyces char- dietary restriction (Ramaiah and Mehendale, 2000).
tarum, which grows predominantly on ryegrass pastures in Tissue repair is a complex process governed by the
Australia and New Zealand. Sporidesmin acts by directly intricate cellular signaling involving chemokines, cyto-
damaging biliary epithelium, producing cell necrosis and kines, growth factors, and nuclear receptors, leading to
degeneration. Bile ducts become occluded with cell debris promitogenic gene expression and cell division. Tissue
and inspissated bile, and periductular fibrosis further repair encompasses regeneration of hepatocytes, hepatic
occludes bile ducts (Rowe, 1989). extracellular matrix, angiogenesis, and other processes
Several plant species cause bile stasis through precipi- necessary to completely restore hepatic structure and
tation of calcium salts of sapogenic glucuronides within function after injury. New insights have emerged over the
bile ducts. The major toxic sapongenins from T. terrestris last quarter century indicating that tissue repair follows a
are diosgenin and yamogenin. These compounds are dose response: at increasing doses of xenobiotics, a
hydrolyzed in the GIT to sapogenins, which are further threshold is reached beyond which repair is delayed or
metabolized before glucuronidation (Burrows and Tyrl, impaired through inhibition of cellular signaling.
2001). Sapogenins directly occlude bile ducts and damage Runaway secondary events then cause tissue destruction,
canalicular membranes. Note that while T. terrestris poi- organ failure and death. Prompt and adequate tissue repair
soning is reported with some frequency in South Africa after toxic injury is critical for recovery. Tissue repair is
and Australia, it is believed that the toxic sapogenins are modulated by species, strain, age, nutrition, disease condi-
either absent or only present in lower concentrations in tion, and other factors, accounting for the marked differ-
T. terrestris growing in the United States (Burrows and ences in individual susceptibility and toxic outcome
Tyrl, 2001). (Ramaiah et al., 1998; Mehendale, 2005).

Inhibition of Tissue Repair Response IDIOSYNCRATIC REACTIONS
Tissue repair is a dynamic response, involving compensa- Idiosyncratic drug reactions occur when sensitization is
tory cell proliferation and tissue regeneration, and is stim- followed by reexposure to a drug, classified as immune-
ulated to recover hepatic structure and function after mediated idiosyncratic hepatotoxicity (Dahm and Jones,
injury. Extensive evidence from rodent models using 1996; Sturgill and Lambert, 1997; Zimmerman, 1999;
structurally and mechanistically diverse hepatotoxicants Treinen-Moslen, 2001). A delay of 3 4 weeks after 1 2
such as acetaminophen, CCl 4 , chloroform, thioacetamide, weeks course of medication (e.g., amoxicillin-clavulanic
trichloroethylene and allyl alcohol have demonstrated that acid) occurs before clinical signs become evident
tissue repair plays a critical role in determining the final (Kaplowitz, 2001; Zimmerman, 1999), but onset is expe-
outcome of toxic insult, i.e., either recovery from injury dited with rechallenge (Dahm and Jones, 1996; Sturgill
and survival or progression of injury leading to liver fail- and Lambert, 1997; Watkins, 1999).
ure and death (Mehendale, 2005). Neoantigens result from adducts formed by interaction
Thioacetamide, originally used as a fungicide, is of reactive drug metabolites with cellular proteins. These
potently hepatotoxic after being bioactivated by cyto- neoantigens are processed by Kupffer cells or other anti-
chrome P450 and/or flavin-containing monooxygenase gen presenting cells, transported to the cell surface, and
systems to sulfine (sulfoxide) and sulfene (sulfone) meta- presented to the immune system. Cell and antibody-
bolites, which cause centrilobular necrosis. Thioacetamide mediated immune responses can cause severe liver dam-
bioactivation is primarily mediated by the cytochrome age. Various drugs believed to cause immune-mediated