Induction of CYP2E1 in testes of isoniazid-treated rats as possible cause of testicular disorders

Shayakhmetova, Ganna M.; Bondarenko, Larysa; Voronina, A.; Анисимова, С. Ю.; Matvienko, Anatoliy V.; Коваленко, В. М.

doi:10.1016/j.toxlet.2015.02.008

Cited by 24 publications

(16 citation statements)

References 44 publications

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“…Many researchers, including our previous report, focused on the core role played by CYP2E1 in INH toxicity (Yue et al, 2004; Cheng et al, 2013; Shayakhmetova et al, 2015; Hassan et al, 2016), we found a positive correlation between INH hepatotoxicity and CYP2E1. Spectacularly, CYP2E1 at its gene expression level almost dwindled in all INH/LPS-treated rats, even those already receiving DEX ( Figure 5E ).…”

Section: Resultssupporting

confidence: 66%

“…INH and its metabolites are responsible for hepatic CYP2E1 induction (Yue et al, 2004; Cheng et al, 2013). Meanwhile, LPS and CYP2E1 shared a unique relationship in which bacterial LPS not only stimulating CYP2E1 expression, but also increases the hepatic sensitivity toward CYP2E1 that further exaggerates INH/LPS toxicity (Lu and Cederbaum, 2010; Cederbaum et al, 2012; Shayakhmetova et al, 2015). Our results clearly indicated that DEX assisted in marginal reduction of CYP2E1 expression, but its capability to fully block CYP2E1 was unsuccessful.…”

Section: Discussionmentioning

confidence: 99%

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Dexamethasone Pretreatment Alleviates Isoniazid/Lipopolysaccharide Hepatotoxicity: Inhibition of Inflammatory and Oxidative Stress

et al. 2017

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Isoniazid (INH) remains a cornerstone key constitute of the current tuberculosis management strategy, but its hepatotoxic potentiality remains a significant clinical problem. Our previous findings succeed to establish a rat model of INH hepatotoxicity employing the inflammatory stress theory in which non-injurious doses of inflammatory-mediating agent bacterial lipopolysaccharides (LPS) augmented the toxicity of INH that assist to uncover the mechanisms behind INH hepatotoxicity. Following LPS exposure, several inflammatory cells are activated and it is likely that the consequences of this activation rather than direct hepatocellular effects of LPS underlie the ability of LPS to augment toxic responses. In this study, we investigated the potential protective role of the anti-inflammatory agent dexamethasone (DEX), a potent synthetic glucocorticoid, in INH/LPS hepatotoxic rat model. DEX pre-treatment successfully eliminates the components of the inflammatory stress as shown through analysis of blood biochemistry and liver histopathology. DEX potentiated hepatic anti-oxidant mechanisms while serum and hepatic lipid profiles were reduced. However, DEX administration was not able to revoke the principal effects of cytochrome P450 2E1 (CYP2E1) in INH/LPS-induced liver damage. In conclusion, this study illustrated the DEX-preventive capabilities on INH/LPS-induced hepatotoxicity model through DEX-induced potent anti-inflammatory activity whereas the partial toxicity seen in the model could be attributed to the expression of hepatic CYP2E1. These findings potentiate the clinical applications of DEX co-administration with INH therapy in order to reduce the potential incidences of hepatotoxicity.

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Section: Resultssupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Dexamethasone Pretreatment Alleviates Isoniazid/Lipopolysaccharide Hepatotoxicity: Inhibition of Inflammatory and Oxidative Stress

et al. 2017

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“…Similarly, CYP2E1 was found to increase liver sensitivity toward LPS and inflammatory mediator toxicity and to potentiate LPS-induced oxidative stress in the liver (57, 58); therefore, both INH and LPS caused overactivation of CYP2E1, which, in return, intensified their toxicity. CYP2E1 involvement in INH toxicity is not limited just to the liver: Shayakhmetova et al declared that the induction of CYP2E1 in rat testicular tissues treated with INH resulted in the triggering and accumulation of ROS that led to testicular toxicity, DNA fragmentation, spermatogenesis disturbances, and male infertility (59). CYP2E1 also had a functional role in bile acid increment through activation of the bile acid synthesis cascade (56).…”

Section: Discussionmentioning

confidence: 99%

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

Hassan

Guo

Yousef

et al. 2016

Antimicrob Agents Chemother

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Isoniazid (INH), since its introduction in the year 1952, still serves as a frontline drug in tuberculosis treatment (1). Despite the fact that INH has been widely used as a first-line antitubercular agent (2, 3), its therapeutic value is usually accompanied by severe hepatotoxicity and lethal hepatic injury (4, 5). Although the pathophysiology of INH-induced liver injury might vary, the toxicity features of the drug, including hepatocellular steatosis, necrosis, and inflammatory infiltration, are nearly consistent (6, 7).Even though extensive studies expounding INH toxicity have been carried out, the exact mechanism of INH hepatotoxicity remains controversial. Among numerous established theories, an inflammatory stress theory has recently been widely used to explain the idiosyncrasy. One hypothesis is that inflammatory stress increases sensitivity to drug-induced liver injury (DILI) (8, 9). In this theory, an incidence of systemic inflammation might reduce the xenobiotic toxicity threshold, which could be easily accomplished by coadministration with an inflammatory agent (10), thus promoting drug toxicity. Lipopolysaccharide (LPS) is an outer cell wall membrane constituent of Gram-negative bacteria that has been comprehensively studied as an inflammatory agent with a major role in bacterial infections (11,12). Previous studies have suggested that LPS might intensify DILI (13-15), and, hence, a possible cornerstone role for LPS in INH-induced hepatotoxicity might be assumed.Oxidative stress, generated from the accumulation of reactive oxygen species (ROS), may be potentiated by different factors, including drugs and inflammation (16,17). In addition, oxidative stress plays a major role in several types of hepatic injury (18). Furthermore, with cytochrome P450 2E1 (CYP2E1) playing a major role in drug metabolism and the pathophysiology of DILI (19) and being considered a principal element in human susceptibility to chemical toxins (20), it plays a central part in oxidative stress, production of ROS, and hepatotoxic injury. Moreover, a previous report proposed that hepatic CYP2E1 plays a fundamental role in the propagation of INH-induced hepatotoxicity, mainly throughout ROS generation (21). Nevertheless, a full understanding of CYP2E1 as a major hepatotoxin-forming, catalyzing enzyme and its influence on INH-induced liver damage has not been completely achieved.Studies of the hepatotoxic mechanisms of INH were previously conducted using different animal models; however, results were accompanied by the absence of certain features of INH toxicity, i.e., delayed onset or inconsistency in severity compared to that in hu-

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“…Therefore, we speculated that flavonoids might be active compounds that can reduce the impact of liver-damaging substances by inhibiting the expression of CYP2E1, which might be one of the hepatoprotective mechanisms of flavonoids. Also, an investigation of the effects of flavonoids on CYP2E1 expression is necessary since some daily foods (purple potato, purple sweet potato, broccoli, bitter gourd, garlic, and tomato), beverages (coffee and cacao polyphenol), and drugs ( Schisandra chinensis , danshen, Gelsemium elegans , isoniazid, diallyl sulfide, sulforaphane, and tamoxifen) are metabolized by CYP2E1 (Vang et al, 1991; Gu et al, 1992; Wargovich, 2006; Wang et al, 2010, 2015; Konstandi et al, 2013; Su et al, 2013; Ahmad et al, 2014; Lu et al, 2014; Zhou et al, 2014, 2015; Shayakhmetova et al, 2015; Suzuki et al, 2015; Jiang et al, 2016a,b). …”

Section: Introductionmentioning

confidence: 99%

Development of an IgY Antibody-Based Immunoassay for the Screening of the CYP2E1 Inhibitor/Enhancer from Herbal Medicines

Jiang

et al. 2016

Front. Pharmacol.

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Cytochrome P450 (CYP) 2E1 is an important enzyme involved in the metabolism of many endogenous and exogenous compounds. It is essential to evaluate the expression of CYP2E1 in the studies of drug–drug interactions and the screening of drugs, natural products, and foodstuffs. The present work is a feasibility study on the development of immunoassays using a specific and sensitive chicken-sourced anti-CYP2E1 IgY antibody. Cloning, expression, and purification of a recombinant CYP2E1 (mice origin) protein were carried out. Anti-CYP2E1 IgY antibodies were generated by immunizing white Leghorn chickens with purified recombinant CYP2E1 protein and were purified by immune affinity chromatography. The IgY titer attained a peak level (≥1:128,000) after the fifth booster injection. For evaluation of the expression of CYP2E1 in different herbal treatment samples, the mice were treated by oral gavage for 3 days with alcohol (50% 15 mL/kg), acetaminophen (APAP, 300 mg/kg), Cornus officinalis extract (100 mg/kg), Alhagi-honey extract (100 mg/kg), Apocynum venetum extract (100 mg/kg), hyperoside (50 mg/kg), isoquercetin (50 mg/kg), 4-hydroxyphenylacetic acid (50 mg/kg), 3-hydroxyphenylacetic acid (50 mg/kg), and 3,4-hydroxyphenylacetic acid (50 mg/kg). The expression of CYP2E1 was determined by Western blot analysis, immunohistochemistry, ELISA, and immunomagnetic beads (IMBs) using anti-CYP2E1 IgY in liver tissue. The results showed that C. officinalis extract, Alhagi-honey extract, A. venetum extract, hyperoside, isoquercetin, and their xenobiotics 4-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, and 3,4-hydroxyphenylacetic acid significantly decreased CYP2E1 levels. Alcohol and APAP treatments significantly increased CYP2E1 levels as analyzed with Western blot analysis, immunohistochemistry, and ELISA. The IMB method is suitable for large-scale screening, and it is a rapid screening (20 min) that uses a portable magnet and has no professional requirements for the operator, which makes it useful for on-the-spot analysis. Considering these results, the anti-CYP2E1 IgY could be applied as a novel research tool in screening for the CYP2E1 inhibitor/enhancer.

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Induction of CYP2E1 in testes of isoniazid-treated rats as possible cause of testicular disorders

Cited by 24 publications

References 44 publications

Dexamethasone Pretreatment Alleviates Isoniazid/Lipopolysaccharide Hepatotoxicity: Inhibition of Inflammatory and Oxidative Stress

Dexamethasone Pretreatment Alleviates Isoniazid/Lipopolysaccharide Hepatotoxicity: Inhibition of Inflammatory and Oxidative Stress

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

Development of an IgY Antibody-Based Immunoassay for the Screening of the CYP2E1 Inhibitor/Enhancer from Herbal Medicines

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