Strain differences in hepatic cytochrome P450 1A and 3A expression between Sprague-Dawley and Wistar rats

Kishida, Taro; Muto, Shin-ichi; Hayashi, Morimoto; Tsutsui, Masaru; Tanaka, Satoru; Murakami, Makoto; Kuroda, Junji

doi:10.2131/jts.33.447

Cited by 45 publications

(26 citation statements)

References 31 publications

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“…Testosterone hydroxylation activity in hepatic microsomes was determined by measuring 6β-, 16α-and 16β-hydroxytestosterone resulting from hydroxylation of testosterone according to a published high-performance liquid chromatography (HPLC) method (Imaoka et al, 1989;Kishida et al, 2008) at 1 mM testosterone (testosterone, hydroxytestosterone; Sigma Chemical Co., St. Louis, MO, USA). The 6β-, 16α-and 16β-testosterone hydroxylation activities are known as indicators of the enzyme activity of CYP3A, CYP2C and CYP2B, respectively, which are major CYP subfamilies.…”

Section: In Vitro Assay Using Hepatic Microsomes Prepared From Rats Tmentioning

confidence: 99%

Increase in covalent binding of 5-hydroxydiclofenac to hepatic tissues in rats co-treated with lipopolysaccharide and diclofenac: involvement in the onset of diclofenac-induced idiosyncratic hepatotoxicity

et al. 2012

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-Diclofenac (DCF), a nonsteroidal anti-inflammatory drug, is well known to induce idiosyncratic hepatotoxicity. Although there remains much to be elucidated about its onset mechanism, it is widely accepted as a hypothesis that idiosyncratic hepatotoxicity arises from a specific immune response to a hapten formed by covalent binding of drugs or their reactive metabolites to hepatic tissues. In this study, we investigated the effects of covalent binding of DCF reactive metabolites to hepatic tissues using a rat model of liver injury induced by co-treatment with lipopolysaccharide (LPS) at a non-hepatotoxic dose. In studies done in vitro using hepatic microsomes prepared from rats treated with LPS alone, 4'-and 5-hydroxylation activities on DCF metabolism and adducts of reactive metabolites to dansyl glutathione (dGSH) were markedly decreased associated with a decrease in total P450 content. However, in studies done in vivo, the LPS/DCF co-treatment significantly increased adducts of 5-hydroxydiclofenac (5-OH-DCF) to rat hepatic tissues and delayed the elimination of 5-OH-DCF from plasma. Furthermore, we investigated the effects of co-treatment on hepatic GSH level in rats. A decrease of hepatic GSH was observed with the LPS/DCF co-treatment but not with LPS or DCF alone. The results suggest that covalent binding of reactive metabolites via 5-OH-DCF to hepatic tissues may play an important role in the onset of DCF-induced idiosyncratic hepatotoxicity, especially under decreased GSH conditions.

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Section: In Vitro Assay Using Hepatic Microsomes Prepared From Rats Tmentioning

confidence: 99%

Increase in covalent binding of 5-hydroxydiclofenac to hepatic tissues in rats co-treated with lipopolysaccharide and diclofenac: involvement in the onset of diclofenac-induced idiosyncratic hepatotoxicity

et al. 2012

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“…Subsequently, Wen et al (2009) showed that NVP is metabolized to a GSH adduct by CYP3A4. Dexamethasone is a highly effective inducer of hepatic CYP3A1 in male Wistar rats and also induces CYP3A2 (Kishida et al, 2008). In addition, 2-and 12-hydroxylations of NVP catalyzed by CYP3A isoforms, as represented by human CYP3A4 and CYP3A5 (Erickson et al, 1999), are potentially bioactivation pathways through the generation of reactive epoxide and quinone methide intermediates (Chen et al, 2008), respectively.…”

Section: Downloaded Frommentioning

confidence: 99%

Quantifying the Metabolic Activation of Nevirapine in Patients by Integrated Applications of NMR and Mass Spectrometries

Srivastava¹,

Lian²,

Maggs³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Nevirapine (NVP), an antiretroviral drug, is associated with idiosyncratic hepatotoxicity and skin reactions. Metabolic pathways of haptenation and immunotoxicity mechanisms have been proposed. NVP is metabolized by liver microsomes to a reactive intermediate that binds irreversibly to protein and forms a GSH adduct. However, no reactive metabolite of NVP, trapped as stable thioether conjugates, has hitherto been identified in vivo. This study has defined the metabolism of NVP with respect to reactive intermediate formation in patients and a rat model of NVP-induced skin reactions. An integrated NMR and mass spectrometry approach has been developed to discover and quantify stable urinary metabolite biomarkers indicative of NVP bioactivation in patients. Two isomeric NVP mercapturates were identified in the urine of HIV-positive patients undergoing standard antiretroviral chemotherapy. The same conjugates were found in rat bile and urine. The mercapturates were isolated from rat bile and characterized definitively by NMR as thioethers substituted at the C-3 and exocyclic C-12 positions of the methylpyrido ring of NVP. It is proposed that NVP undergoes bioactivation to arene oxide and quinone methide intermediates. The purified major mercapturate was quantified by NMR and used to calibrate a mass spectrometric assay of the corresponding metabolite in patient urine. This is the first evidence for metabolic activation of NVP in humans, and only the second minimum estimate in patients of bioactivation of a widely prescribed drug associated with idiosyncratic toxicities. The method can be used as a template for comparative estimations of bioactivation of any drug in patients.

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“…The LD50 was determined by linear regression analysis using the SPSS Science statistical software (v. 15 …”

Section: Discussionmentioning

confidence: 99%

“…the authors administered the extract orally for 90 days at doses of 1,000, 100, and 10 mg/kg/day; however, their study did not report that the extract produces a modulator effect. Some of the cytochromes studied so far include the following: 1A1 Kishida et al (2008) demonstrated that DEX is a selective inducer of CYP3a1, and that this induction is favored in Wistar rats. One of the strengths of the present study is that all of the groups were maintained, and that the same administration route was employed (Badal et al, 2011;Kondo et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Effect of Ruta Chalepensis Extract on Hepatic Cytochrome 3a1 in Rats

Martínez-Pérez

Hernández-Terán

Serrano-Gallardo

2017

Afr J Tradit Complement Altern Med

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Background: Since the time when drugs began to be used, it became evident that they could produce a therapeutic effect, but also a clinical condition of toxicity or no effect at all on humans, despite using the same doses in different patients. Such untoward effects were termed "drug idiosyncrasy" and also "idiosyncratic drug effects", but the factors producing such diverse responses were never taken into account. Materials and Methods: Ruta chalepensis L. (fringed rue) is an herbaceous plant of the Rutaceae family used in traditional medicine due to its properties, such as its analgesic and antipyretic effects. This study used 25 male rats divided into five groups. Plant extract was administered to Groups 1 and 2 at doses of 100 and 30 mg/kg/day, respectively, for three days; Group 3 was administered 100 mg/kg/day of dexamethasone (DEX), as well as 100 mg/kg/day of Ruta chalepensis extract; Group 4 was administered 100 mg/kg/day of DEX and treated as positive control; Group 5 was treated as negative control and was administered a physiological solution. Twenty-four hours after the the last dose, the animals were sacrificed and their livers were extracted. Results: The aqueous extract of Ruta chalepensis, intraperitoneally administered, was able to induce cytochrome 3A1 in doses of 30 mg/kg/day, and a greater inducing effect occurs when the plant is co-administered in doses of 100 mg/kg/day with dexamethasone. Conclusion: This study suggests that aqueous extract of Ruta chalepensis can induce cytochrome 3a1. This study helps provide a better understanding of CYP3a regulation. Future in vitro work is needed to determine the compounds that produce the cytochrome modulation.

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Strain differences in hepatic cytochrome P450 1A and 3A expression between Sprague-Dawley and Wistar rats

Cited by 45 publications

References 31 publications

Increase in covalent binding of 5-hydroxydiclofenac to hepatic tissues in rats co-treated with lipopolysaccharide and diclofenac: involvement in the onset of diclofenac-induced idiosyncratic hepatotoxicity

Increase in covalent binding of 5-hydroxydiclofenac to hepatic tissues in rats co-treated with lipopolysaccharide and diclofenac: involvement in the onset of diclofenac-induced idiosyncratic hepatotoxicity

Quantifying the Metabolic Activation of Nevirapine in Patients by Integrated Applications of NMR and Mass Spectrometries

In Vivo Effect of Ruta Chalepensis Extract on Hepatic Cytochrome 3a1 in Rats

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