The crucial protective role of glutathione against tienilic acid hepatotoxicity in rats

Nishiya, Takayoshi; Mori, Kazuhiko; Hattori, Chiharu; Kang, Kai; Kataoka, Hiroko; Masubuchi, Noriko; Jindo, Toshimasa; Manabe, Sunao

doi:10.1016/j.taap.2008.06.024

Cited by 20 publications

(20 citation statements)

References 47 publications

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“…2A). Many researchers have applied GSH-depleted animal models using BSO to evaluate the hepatotoxic potential of several drugs (Nishiya et al, 2008;Shimizu et al, 2009Shimizu et al, , 2011Kobayashi et al, 2012a). Therefore, BSO (700 mg/kg) was intraperitoneally injected 2 hours prior to the oral CBZ administration; however, the plasma ALT levels were not increased ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Some researchers have established animal models of drug-induced liver injury, such as trovafloxacilin and sulindac, using lipopolysaccharide to study immune-mediated mechanisms (Shaw et al, 2007, Zou et al, 2009). In addition, it has been reported that GSH-depleted animal models using L-buthionine sulfoximine (BSO), which is an inhibitor of GSH synthesis, are useful for inducing sensitization to liver injury by such drugs as methimazole, tienilic acid, amodiaquine, and ticlopidine via reactive metabolite formations (Nishiya et al, 2008;Shimizu et al, 2009Shimizu et al, , 2011Kobayashi et al, 2012a).…”

Section: Introductionmentioning

confidence: 99%

“…In this study, BSO was used to deplete GSH to develop CBZ-induced liver injury in rats because BSO is known to be a specific inhibitor of g-glutamylcysteine synthetase, a rate-limiting enzyme of GSH synthesis (Griffith and Meister 1979), and can decrease the hepatic GSH content in rats (Gao et al, 2010). Many researchers have applied the GSH-depleted animal model using BSO to evaluate hepatotoxic potential for several drugs that are known to generate electrophilic reactive metabolites, such as methimazole, tienilic acid, amodiaquine, and ticlopidine (Nishiya et al, 2008;Shimizu et al, 2009Shimizu et al, , 2011Kobayashi et al, 2012a). In this study, several rats administered CBZ at a dose of 600 mg/kg or 800 mg/kg in combination with BSO on the 5th day showed severe hepatotoxicity, whereas rats administered CBZ alone showed no hepatotoxicity (Fig.…”

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confidence: 99%

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Carbamazepine-Induced Liver Injury Requires CYP3A-Mediated Metabolism and Glutathione Depletion in Rats

et al. 2015

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Carbamazepine (CBZ) is widely used as an antiepileptic agent and causes rare but severe liver injury in humans. It has been generally recognized that reactive metabolites formed via the metabolic activation reaction contribute to the onset of liver injuries by several drugs. However, the role of CBZ metabolism in the development of liver injury is not fully understood. In this study, we developed a novel rat model of CBZ-induced liver injury and attempted to elucidate the associated mechanisms by focusing on the metabolism of CBZ. The repeated administration of CBZ for 5 days in combination with L-buthionine sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, resulted in increases in the plasma alanine aminotransferase (ALT) levels and centrilobular necrosis in the liver that were observed in various degrees. The CBZ and 2-hydroxy-CBZ concentrations in the plasma after the last CBZ administration were lower in the rats with high plasma ALT levels compared with those with normal plasma ALT levels, showing the possibility that the further metabolism of CBZ and/ or 2-hydroxy-CBZ is associated with the liver injury. Although a single administration of CBZ did not affect the plasma ALT levels, even when cotreated with BSO, pretreatment with dexamethasone, a CYP3A inducer, increased the plasma ALT levels. In addition, the rats cotreated with troleandomycin or ketoconazole, CYP3A inhibitors, suppressed the increased plasma ALT levels. In conclusion, reactive metabolite(s) of CBZ produced by CYP3A under the GSH-depleted condition might be involved in the development of liver injury in rats.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Carbamazepine-Induced Liver Injury Requires CYP3A-Mediated Metabolism and Glutathione Depletion in Rats

et al. 2015

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“…in vitro (Gan et al, 2005) in vivo GSH (LPS) (Shaw et al, 2007;Tukov et al, 2007;Lu et al, 2012) LPS GSH (Shimizu et al, 2009;Nishiya et al, 2008 DPH (Dhar et al, 1974;Haruda, 1979;Taylor et al, 1984 (Munns et al, 1997) 4'-HPPH CYP GSH (Munns et al, 1997;Roy and Snodgrass, 1988;1990…”

Section: Dna (Gsh)mentioning

confidence: 99%

Role of cytochrome P450-mediated metabolism and identification of novel thiol-conjugated metabolites in mice with phenytoin-induced liver injury

Iwamura¹,

Tsuneyama

Fukami

et al. 2015

Toxicology Letters

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“…It should be noted that, to maintain consistency, tienilic acid concentrations need to be adjusted for each new HLM pool (data not shown). Tienilic acid-treated microsomes should be diluted and/or washed to minimize unbound molecules, because tienilic acid has been reported to react with protein nucleophiles, to deplete glutathione levels, and to up-regulate genes involved in oxidative stress responses and phase II drug metabolism (Belghazi et al, 2001;López-García et al, 2005;Nishiya et al, 2008); this is most applicable to hepatocyte preparations.…”

Section: Kinetic Parameters Of the Effect Of Tienilic Acid On Non-cypmentioning

confidence: 99%

Development of an In Vitro System with Human Liver Microsomes for Phenotyping of CYP2C9 Genetic Polymorphisms with a Mechanism-Based Inactivator

Flora

Tracy

2011

Drug Metab Dispos

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ABSTRACT:Polymorphisms in cytochrome P450 enzymes can significantly alter the rate of drug metabolism, as well as the extent of drug-drug interactions. Individuals who homozygotically express the CYP2C9*3 allele (I359L) of CYP2C9 exhibit ϳ70 to 80% reductions in the oral clearance of drugs metabolized through this pathway; the reduction in clearance is ϳ40 to 50% for heterozygotic individuals. Although these polymorphisms result in a decrease in the activity of individual enzyme molecules, we hypothesized that decreasing the total number of active enzyme molecules in an in vitro system (CYP2C9*1/*1 human liver microsomes) by an equivalent percentage could produce the same net change in overall metabolic capacity. To this end, the selective CYP2C9 mechanismbased inactivator tienilic acid was used to reduce irreversibly the total CYP2C9 activity in human liver microsomes. Tienilic acid concentrations were effectively titrated to produce microsomal preparations with 43 and 73% less activity, mimicking the CYP2C9*1/*3 and CYP2C9*3/*3 genotypes, respectively. With probe substrates specific for other major cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), no apparent changes in the rate of metabolism were noted for these enzymes after the addition of tienilic acid, which suggests that this model is selective for CYP2C9. In lieu of using rare human liver microsomes from CYP2C9*1/*3 and CYP2C9*3/*3 individuals, a tienilic acid-created knockdown in human liver microsomes may be an appropriate in vitro model to determine CYP2C9-mediated metabolism of a given substrate, to determine whether other drug-metabolizing enzymes may compensate for reduced CYP2C9 activity, and to predict the extent of genotypedependent drug-drug interactions.

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The crucial protective role of glutathione against tienilic acid hepatotoxicity in rats

Cited by 20 publications

References 47 publications

Carbamazepine-Induced Liver Injury Requires CYP3A-Mediated Metabolism and Glutathione Depletion in Rats

Carbamazepine-Induced Liver Injury Requires CYP3A-Mediated Metabolism and Glutathione Depletion in Rats

Role of cytochrome P450-mediated metabolism and identification of novel thiol-conjugated metabolites in mice with phenytoin-induced liver injury

Development of an In Vitro System with Human Liver Microsomes for Phenotyping of CYP2C9 Genetic Polymorphisms with a Mechanism-Based Inactivator

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