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Title:The use of glutathione in canine itraconazole-associated hepatotoxicity
Author(s):Kirk, Natalie M
Advisor(s):Reinhart, Jennifer M
Contributor(s):Selting, Kimberly A; Vieson, Miranda D
Department / Program:Vet Clinical Medicine
Discipline:VMS-Veterinary Clinical Medcne
Degree Granting Institution:University of Illinois at Urbana-Champaign
Abstract:Azole antifungals are essential and effective drugs in treating a variety of superficial and systemic mycoses in veterinary species. Their activity is attributable to inhibition of fungal ergosterol by targeting cytochrome P450-dependent sterol 14α-demethylase. The most commonly used azoles in small animal veterinary medicine are itraconazole (ITZ), fluconazole (FCZ), and ketoconazole (KTZ). Owing to its greater selectivity for fungal ergosterol over mammalian cholesterol, ITZ has fewer adverse effects than KTZ. Additionally, it has a broader spectrum of activity than both KTZ and FCZ. For this reason, ITZ is used to treat a variety of fungal infections in dogs and is the treatment of choice for canine blastomycosis, a severe systemic mycosis endemic in the Midwest. Despite its efficacy, ITZ is associated with a number of adverse reactions including hepatotoxicity. The mechanism of this toxicity is unknown. As with many drugs, oxidative damage may play an important role in ITZ-associated toxicity. In rodent studies, ITZ administration increases levels of myeloperoxidase and nitric oxide and decreases levels of hepatic glutathione (GSH) and other antioxidants. Based on this, antioxidant therapy could potentially prevent or treat ITZ-associated hepatotoxicity. Antioxidant hepatoprotectants are commonly used for a variety of liver diseases in veterinary medicine. These include GSH precursors like S-adenosylmethionine (SAMe) and N-acetylcysteine (NAC) and other antioxidants including silybin, vitamin E, and vitamin C. However, no studies have investigated the efficacy of this practice and scientific evidence is needed to provide a basis for their use. A reliable in vitro model to establish these principles is required prior to testing compounds in animal subjects. The objective of this work was to develop an in vitro primary canine hepatocyte model of ITZ-associated hepatotoxicity and evaluate the effect of GSH using the model. We hypothesized that GSH would ameliorate ITZ-associated hepatocyte death in vitro. The results demonstrate dose and time-dependent cytotoxicity of cryopreserved primary canine hepatocytes exposed to ITZ. Pre-incubation with GSH caused a dose-dependent decrease in toxicity. This study establishes primary canine hepatocytes as an appropriate in vitro model for ITZ-associated toxicity. GSH pre-treatment partially ameliorates the toxic effect, suggesting a possible role for GSH and oxidative stress in the pathogenesis of toxicity. These findings support continued investigation into other antioxidants as prevention and/or treatment for ITZ-associated hepatotoxicity and their rational clinical use.
Issue Date:2020-05-13
Rights Information:Copyright 2020 Natalie Kirk
Date Available in IDEALS:2020-08-26
Date Deposited:2020-05

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