Involvement of oxidative stress and immune- and inflammation-related factors in azathioprine-induced liver injury

Matsuo, Kentaro; Sasaki, Eita; Higuchi, Satonori; Takai, Shohei; Tsuneyama, Koichi; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1016/j.toxlet.2013.10.025

Cited by 32 publications

(28 citation statements)

References 40 publications

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“…[8] Furthermore, increase in ROS (as hydroxyl radical) could be involved in AZA toxicity. [32] In contrast, mean relative liver weights were decreased in the rats treated with CFME or FSME before AZA treatment. Furthermore, marked improvements in the histopathological changes were noticed, due to their antioxidant abilities.…”

Section: Discussionmentioning

confidence: 93%

“…[8] 6-MP is further converted into 6-thiouric acid by xanthine oxidases (XO). It has been reported that XO has the potential to generate ROS in human hepatocytes [32] and that the oxidation of 6-MP by XO is involved in the AZA-induced liver injury in patients with inflammatory bowel disease. [33] Another metabolic pathway converts 6-MP into 6-thioinosine monophosphate via hypoxanthine-guanine phosphoribosyl transferase, and this intermediate is then metabolized into active 6-thioguanine nucleotides (6-TGNs).…”

Section: Discussionmentioning

confidence: 99%

“…[35] The metabolic conversion of 6-MP into 6-thiouric acid via XO, which is a critical source of ROS, potentially leads to hepatotoxicity. [32] It has been suggested that ROS production by mitochondria caused by thiopurines could damage the membranes and macromolecules. [8] In the present study, the oxidative injury in AZA-treated animals was evident from the significant decline in GSH and TAC levels.…”

Section: Discussionmentioning

confidence: 99%

“…These findings are in agreement with previous studies, which recorded the involvement of oxidative stress and lipid peroxidation in AZA-induced liver injury. [32,36] In hepatocytes, GSH is consumed during the metabolism of AZA to 6-MP. The mechanism of AZA toxicity to hepatocytes involves the depletion of GSH leading to mitochondrial injury with profound depletion of ATP and cell death by necrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the decrease in GSH induced by AZA administration may be caused by the exhaustion of GSH during ROS scavenging. [32] Lipid peroxidation, as well as altered levels of some endogenous scavengers, are taken as indirect in vivo reliable indices for the contribution of free radical generation and in turn oxidative stress. [37] It has already been demonstrated that the depletion of GSH precedes the induction of lipid peroxidation.…”

Section: Discussionmentioning

confidence: 99%

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Preventive role of chamomile flowers and fennel seeds extracts against liver injury and oxidative stress induced by an immunosuppressant drug in rats

Mannaa¹,

Ibrahim²,

Ibrahim³

et al. 2015

Hepatoma Res

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Aim: The present study was conducted to investigate the protective effect of chamomile fl owers methanolic extract (CFME) and fennel seeds methanolic extract (FSME) on azathioprine (AZA), an immunosuppressant drug, which induced a liver injury and oxidative stress in rats. Methods: Rats were divided into 6 groups (8 rats each) and treated orally for 28 consecutive days as follows. Group 1: rats were given normal saline and used as controls; group 2: rats treated with CFME (200 mg/kg); group 3: rats treated with FSME (200 mg/kg); group 4: rats treated with AZA (25 mg/kg); and groups 5 and 6: rats treated with CFME (200 mg/kg) or FSME (200 mg/kg) 15 min prior to AZA (25 mg/kg) treatment. At the end of experimental period, blood and liver samples were collected from all groups for biochemical analysis and histological examination. Results: The obtained data revealed that AZA-induced hepatic injury in the rats as evidenced by the signifi cant increase in serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, cholesterol, and direct bilirubin as well as hepatic malondialdehyde level accompanied with signifi cant decrease in reduced glutathione content and total antioxidant capacity in the liver. Moreover, body weight gain showed the signifi cant decrease and relative liver weight showed the signifi cant increase on AZA treatment. The sequential signifi cant changes in biochemical parameters were accompanied by severe histological changes in the liver tissue, including hepatocytes disorganization with pyknotic nuclei, fatty degeneration, congestion, fi brosis, and bile duct necrosis around the portal tract. The areas of hemorrhages in blood vessels and in between hepatocytes were also seen. However, the results showed the potential hepatoprotective effects of CFME and FSME against AZA-induced liver injury and oxidative stress. They succeeded in restoring the biochemical parameters and improving the histological picture of the liver. This improvement was more pronounced in the rats pretreated with FSME. Conclusion: It could be concluded that CFME and FSME have hepatoprotective potentials against AZA probably due to their antioxidant properties and radical scavenging activity.Key words: Azathioprine; chamomile fl owers; fennel seeds; liver; oxidative stress Preventive role of chamomile fl owers and fennel seeds Preventive role of chamomile fl owers and fennel seeds extracts against liver injury and oxidative stress induced by an extracts against liver injury and oxidative stress induced by an immunosuppressant drug in rats immunosuppressant drug in rats This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Preventive role of chamomile flowers and fennel seeds extracts against liver injury and oxidative stress induced by an immunosuppressant drug in rats

Mannaa¹,

Ibrahim²,

Ibrahim³

et al. 2015

Hepatoma Res

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Principles of Systemic Therapy

Tidman

Smith

2016

Rook's Textbook of Dermatology, Ninth Edition

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This chapter on systemic dermatological therapy aims to provide practising dermatologists with sufficient information about the most frequently used systemic medications to enable these to be used for treating skin disease to the maximum benefit and minimum detriment to their patients. The introduction covers general aspects of systemic therapy, including patient selection and education, risk reduction measures and the importance of good record keeping. Thereafter follows a detailed review of immunomodulatory and antimicrobial drugs, including antihistamines, antimalarial agents, azathioprine, ciclosporin, colchicine, dapsone, fumaric acid esters, glucocorticoids, hydroxycarbamide, methotrexate, mycophenolate mofetil, potassium iodide, protein therapies (biological drugs and intravenous immunoglobulin), retinoids, thalidomide, antibiotics, antifungal agents and antiviral drugs. The profile of each individual drug includes its pharmacological properties (formula and structure, pharmacodynamics, pharmacokinetics and, where relevant, pharmacogenetic aspects), potential adverse effects, contraindications, cautions, drug–drug interactions, pre‐treatment screening, dosage regimens, monitoring requirements and its range of licensed and off‐label dermatological usage.

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