Page 287 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

254 SECTION | II Organ Toxicity

VetBooks.ir Hepatocyte halothane (Trepanier, 2013). A proposed explanation for the delayed
onset of clinical signs is that mitochondrial damage is not
CYP2E1
manifested until a threshold has been reached, then cell
Oxidative metabolism
death occurs. Genetic polymorphisms in activation of
Trifluroacetylated microsomal proteins detoxifying enzymes have been associated with increased
susceptibility to idiosyncratic drug reactions in some peo-
ple, further implicating the role of oxidative stress
(Stirnimann et al., 2010).
Expression on hepatocyte surface Other idiosyncratic reactions of veterinary importance
include diazepam in cats, which could be based on
humoral or T-cell mediated immunity (Center et al.,
1996; Trepanier, 2013). The clinical presentation in cats
is similar to that described with carprofen in dogs.
Idiosyncratic reactions to sulfonamides occur in about
Cellular sensitization 0.25% of dogs and a variety of organ systems are
affected, hepatopathy being the third most reported
sequela. Other effects include polyarthropathy, which pre-
Hepatotoxicity
dominates in Doberman pinschers, thrombocytopenia,
FIGURE 15.6 Postulated mechanism of immune-mediated halothane pyrexia and dermal drug eruptions. A reactive metabolite
hepatotoxicity. Halothane-mediated hepatitis is the best example for of sulfonamide binds to protein creating a hapten and
immune-mediated liver damage. Oxidative pathway yields trifluoroace- may activate drug-specific T-cells, as occurs in humans
tylchloride, which can react with microsomal proteins to form a neoanti-
gen which then can generate immune response leading to hepatic injury. (Trepanier, 2013). Methimazole and carbimazole are anti-
thyroid drugs that have caused idiosyncratic reactions in
cats and can cause hepatocellular and cholestatic liver
idiosyncratic reactions in humans include halothane, damage, thrombocytopenia or neutropenia, or pruritis
diclofenac, phenytoin, and sulfonamides (Sturgill and within a month of initiating therapy (Trepanier, 2013).
Lambert, 1997; Watkins, 1999; Zimmerman, 1999; Recently, zonisamide has been reported to cause acute
Treinen-Moslen, 2001). The idiosyncratic reaction to hal- liver failure after 10 20 days of dosing (Trepanier, 2013;
othane has been well studied (Fig. 15.6). Weingarten and Sande, 2015).
Clinical signs of the idiosyncratic reaction to carpro- Some idiosyncratic drug reactions are associated with
fen, an NSAID, in dogs include anorexia, vomiting, and very long latency (up to 12 months), but are usually not
icterus and occur approximately 20 days following the associated with features of hypersensitivity and have var-
first exposure to the drug. Signs do not correlate with iable response to rechallenge. These are classified as
drug dose. Affected dogs have elevated alanine transami- nonimmuno-mediated idiosyncratic reactions (Kaplowitz,
nase, aspartate transaminase, alkaline phosphates and 2001). Examples of drugs that are known to cause this
serum total bilirubin. There is mild to severe bridging type of idiosyncratic reaction include troglitazone,
hepatocyte degeneration and necrosis with evidence of valproate, amiodarone, ketoconazole, disulfiram, and iso-
apoptosis. Mild to moderate periportal inflammation is niazid. However, some involvement of allergic mecha-
reported. Spayed female dogs are overrepresented among nism cannot be completely rejected in these drugs, thus
the affected (MacPhail et al., 1998). This idiosyncratic this classification should still be viewed as tentative
reaction to carprofen is most likely similar to that of (Kaplowitz, 2005).
diclofenac in humans. Diclofenac generates reactive meta-
bolites and forms a hapten (Trepanier, 2013).
Methimazole is another example of agents causing idi- CONCLUDING REMARKS AND
osyncratic hepatotoxicosis affecting humans and cats. FUTURE DIRECTIONS
Patients usually present with icterus. The hepatic effect
appears to be associated with metabolism by hepatic fla- Research has focused on understanding the different
vin monooxygenase to a reactive N-methylthiourea mechanisms for chemical-induced liver injury.
metabolite. GSH depletion is believed to play a role in Researchers have attempted to understand the molecular
human cases (Trepanier, 2013). basis for injury and the contribution of individual cell
Many drugs implicated in idiosyncratic liver injury are types to ultimate hepatic pathology. Recently, techniques
known to affect mitochondrial function (Stirnimann et al., such as microarray-based toxicogenomics, 2D gel electro-
2010). Part of the mechanism of injury due to diclofenac phoresis, mass spectrometry-based proteomics and
in humans could be due to mitochondrial injury 1 H-NMR spectroscopy-based metabonomics have