Nitrosative Stress and Lipid Homeostasis as a Mechanism for Zileuton Hepatotoxicity and Resistance in Genetically Sensitive Mice

Abstract

Zileuton is an orally active inhibitor of leukotriene synthesis for maintenance treatment of asthma, for which clinical usage has been associated with idiosyncratic liver injury. Mechanistic understanding of zileuton toxicity is hampered by the rarity of the cases and lack of an animal model. A promising model for mechanistic study of rare liver injury is the Diversity Outbred (J:DO) mouse population, with genetic variation similar to that found in humans. In this study, female DO mice were administered zileuton or vehicle daily for 7 days (i.g.). Serum liver enzymes were elevated in the zileuton group, with marked interindividual variability in response. Zileuton exposure-induced findings in susceptible DO mice included microvesicular fatty change, hepatocellular mitosis, and hepatocellular necrosis. Inducible nitric oxide synthase and nitrotyrosine abundance were increased in livers of animals with necrosis and those with fatty change, implicating nitrosative stress as a possible injury mechanism. Conversely, DO mice lacking adverse liver pathology following zileuton exposure experienced decreased hepatic concentrations of resistin and increased concentrations of insulin and leptin, providing potential clues into mechanisms of toxicity resistance. Transcriptome pathway analysis highlighted mitochondrial dysfunction and altered fatty acid oxidation as key molecular perturbations associated with zileuton exposure, and suggested that interindividual differences in cytochrome P450 metabolism, glutathione-mediated detoxification, and farnesoid X receptor signaling may contribute to zileuton-induced liver injury (ZILI). Taken together, DO mice provided a platform for investigating mechanisms of toxicity and resistance in context of ZILI which may lead to targeted therapeutic interventions.

Natural variation suggests candidate genes underlying Caenorhabditis elegans susceptibility to diverse toxicants

“…Several genetically diverse animal populations have been used to identify genetic factors that contribute to differences in susceptibility among individuals (Rusyn et al ., 2022). For example, studies using genetically diverse rodent populations have identified candidate susceptibility genes involved in xenobiotic metabolism (Church et al ., 2014; Nguyen et al ., 2017; Yoo et al ., 2015; You et al ., 2020), immune response (Harrill et al ., 2009), chromatin structure (Koturbash et al ., 2011), and tissue repair pathways (Harrill et al ., 2012; Tsuchiya et al ., 2012; Harrill et al ., 2018). Although genetically diverse rodent populations are a powerful mammalian model for toxicological studies, the model is inherently low-throughput, making it less suited for large-scale experimentation.…”

Natural variation suggests candidate genes underlying Caenorhabditis elegans susceptibility to diverse toxicants

“…Several genetically diverse animal populations have been used to identify genetic factors that contribute to differences in susceptibility among individuals (Rusyn et al ., 2022). For example, studies using genetically diverse rodent populations have identified candidate susceptibility genes involved in xenobiotic metabolism (Church et al ., 2014; Nguyen et al ., 2017; Yoo et al ., 2015; You et al ., 2020), immune response (Harrill et al ., 2009), chromatin structure (Koturbash et al ., 2011), and tissue repair pathways (Harrill et al ., 2012; Tsuchiya et al ., 2012; Harrill et al ., 2018). Although genetically diverse rodent populations are a powerful mammalian model for toxicological studies, the model is inherently low-throughput, making it less suited for large-scale experimentation.…”

CRISPR/Cas9-mediated neuronal deletion of 5-lipoxygenase alleviates deficits in mouse models of epilepsy

“…Pharmacological inhibition of Alox5 by the FDA approved inhibitor zileuton significantly attenuated seizure-induced neuronal impairment via abrogating ferroptosis process [10] , indicating a critical role of neuronal Alox5 in the modulation of seizure behavior. However, the severe toxic effect such as liver injury brings great clinical challenges regarding the usage of zileuton [11] . Given that neuronal Alox5 contributes to the brain injury post seizure, it is rational to speculate that neuron-specific depletion of Alox5 by gene editing has therapeutic effects on seizure activity and epileptic progression with satisfactory biosafety.…”

Role of Farnesoid X Receptor in the Pathogenesis of Respiratory Diseases

“…In addition, FXR can be used as a potential therapeutic target for several diseases [ 13 , 14 ]. Recent studies have suggested that FXR may play a considerable role in the physiological and pathological aspects of the respiratory system [ 15 – 17 ]. In this article, we provide an overview of the internal relationship between FXR and respiratory diseases to track the progress that has been achieved thus far in this direction and suggest potential therapeutic prospects of FXR in respiratory diseases.…”

Natural variation suggests candidate genes underlying Caenorhabditis elegans susceptibility to diverse toxicants

“…Several genetically diverse animal populations have been used to identify genetic factors that contribute to differences in susceptibility among individuals (Rusyn et al ., 2022). For example, studies using genetically diverse rodent populations have identified candidate susceptibility genes involved in xenobiotic metabolism (Church et al ., 2014; Nguyen et al ., 2017; Yoo et al ., 2015; You et al ., 2020), immune response (Harrill et al ., 2009), chromatin structure (Koturbash et al ., 2011), and tissue repair pathways (Harrill et al ., 2012; Tsuchiya et al ., 2012; Harrill et al ., 2018). Although genetically diverse rodent populations are a powerful mammalian model for toxicological studies, the model is inherently low-throughput, making it less suited for large-scale experimentation.…”

CRISPR/Cas9-mediated neuronal deletion of 5-lipoxygenase alleviates deficits in mouse models of epilepsy

“…Pharmacological inhibition of Alox5 by the FDA approved inhibitor zileuton significantly attenuated seizure-induced neuronal impairment via abrogating ferroptosis process [10] , indicating a critical role of neuronal Alox5 in the modulation of seizure behavior. However, the severe toxic effect such as liver injury brings great clinical challenges regarding the usage of zileuton [11] . Given that neuronal Alox5 contributes to the brain injury post seizure, it is rational to speculate that neuron-specific depletion of Alox5 by gene editing has therapeutic effects on seizure activity and epileptic progression with satisfactory biosafety.…”

Role of Farnesoid X Receptor in the Pathogenesis of Respiratory Diseases

“…In addition, FXR can be used as a potential therapeutic target for several diseases [ 13 , 14 ]. Recent studies have suggested that FXR may play a considerable role in the physiological and pathological aspects of the respiratory system [ 15 – 17 ]. In this article, we provide an overview of the internal relationship between FXR and respiratory diseases to track the progress that has been achieved thus far in this direction and suggest potential therapeutic prospects of FXR in respiratory diseases.…”

Natural variation suggests candidate genes underlying Caenorhabditis elegans susceptibility to diverse toxicants

“…Several genetically diverse animal populations have been used to identify genetic factors that contribute to differences in susceptibility among individuals (Rusyn et al ., 2022). For example, studies using genetically diverse rodent populations have identified candidate susceptibility genes involved in xenobiotic metabolism (Church et al ., 2014; Nguyen et al ., 2017; Yoo et al ., 2015; You et al ., 2020), immune response (Harrill et al ., 2009), chromatin structure (Koturbash et al ., 2011), and tissue repair pathways (Harrill et al ., 2012; Tsuchiya et al ., 2012; Harrill et al ., 2018). Although genetically diverse rodent populations are a powerful mammalian model for toxicological studies, the model is inherently low-throughput, making it less suited for large-scale experimentation.…”

CRISPR/Cas9-mediated neuronal deletion of 5-lipoxygenase alleviates deficits in mouse models of epilepsy

“…Pharmacological inhibition of Alox5 by the FDA approved inhibitor zileuton significantly attenuated seizure-induced neuronal impairment via abrogating ferroptosis process [10] , indicating a critical role of neuronal Alox5 in the modulation of seizure behavior. However, the severe toxic effect such as liver injury brings great clinical challenges regarding the usage of zileuton [11] . Given that neuronal Alox5 contributes to the brain injury post seizure, it is rational to speculate that neuron-specific depletion of Alox5 by gene editing has therapeutic effects on seizure activity and epileptic progression with satisfactory biosafety.…”

Role of Farnesoid X Receptor in the Pathogenesis of Respiratory Diseases

“…In addition, FXR can be used as a potential therapeutic target for several diseases [ 13 , 14 ]. Recent studies have suggested that FXR may play a considerable role in the physiological and pathological aspects of the respiratory system [ 15 – 17 ]. In this article, we provide an overview of the internal relationship between FXR and respiratory diseases to track the progress that has been achieved thus far in this direction and suggest potential therapeutic prospects of FXR in respiratory diseases.…”