Differential toxic effects of azathioprine, 6-mercaptopurine and 6-thioguanine on human hepatocytes

Petit, Elise; Langouët, Sophie; Akhdar, Hanane; Nicolas-Nicolaz, Christophe; Guillouzo, André; Morel, Franck

doi:10.1016/j.tiv.2007.12.004

Cited by 70 publications

(53 citation statements)

References 22 publications

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“…[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). [34] 6-TGNs are also responsible for the cytotoxic side effects. [35] The metabolic conversion of 6-MP into 6-thiouric acid via XO, which is a critical source of ROS, potentially leads to hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…Hybrids of quinolines and anticancer agents Thiopurines, like 6-mercaptopurines, are cytotoxic prodrugs that hinder nucleic acid synthesis by inhibiting enzymes involved in the de novo purine synthetic pathway, 178 and they are often used in cancer treatment and as immunosupressors. [179][180] Conjugation of the sodium salt of 6-mercaptopurine with (7-chloroquinolin-4-ylamino)alkyl methanesulfonate afforded hybrids 99 and 100 ( Figure 49), which were evaluated in vivo against P. berghei in a murine malaria model to determine their antiplasmodial efficacy. Compound 99 displayed the best antimalarial profile, after 7 days there was more than 70% inhibition of parasite multiplication (when using doses of 5 mg/kg/day for 4 days).…”

Section: Figure 46mentioning

confidence: 99%

Quinoline-based antimalarial hybrid compounds

Vandekerckhove

D’hooghe

2015

Bioorganic & Medicinal Chemistry

196

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Quinoline-containing compounds, such as quinine and chloroquine, have a long-standing history as potent antimalarial agents. However, the increasing resistance of the Plasmodium parasite against these drugs and the lack of licensed malaria vaccines have forced chemists to develop synthetic strategies toward novel biologically active molecules. A strategy that has attracted considerable attention in current medicinal chemistry is based on the conjugation of two biologically active molecules into one hybrid compound. Since quinolines are considered to be privileged antimalarial building blocks, the synthesis of quinoline-containing antimalarial hybrids has been elaborated extensively in recent years. This review provides a literature overview of antimalarial hybrid molecules containing a quinoline core, covering publications between 2009 and 2014.

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“…6-Mercaptopurine (6-MP) is a purine derivate, widely used for the therapy of acute lymphoblastic leukemia by inhibiting purine metabolism [1][2][3]. Because the therapeutic effectiveness of 6-MP was dependent upon a series of biochemical transformations [4], the 6-MP plasma concentration was found to be highly variable with individual differences [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…The peak current ratios of the 50th CV to 1st CV for [Co(phen)2 (tatp)] 3+ and [Co(phen) 3 ] 3+ are estimated to be 9.20 and 9.16. And the E°0 and k f values are 0.279 V and 6.61 s À1 for [Co(phen) 2 (tatp)] 3+ , 0.241 V and 1.93 s À1 for [Co(phen)3 ] 3+ , respectively. This result indicates a difference of [Co(phen) 2 L] 3+ on DNA-MWCNT/GC and SDS-MWCNT/GC electrodes.…”

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confidence: 99%

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Fabrication and evaluation of [Co(phen)2L]3+-modified DNA-MWCNT and SDS-MWCNT electrodes for electrochemical detection of 6-mercaptopurine

Zhou

Gan

et al. 2012

Journal of Electroanalytical Chemistry

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Differential toxic effects of azathioprine, 6-mercaptopurine and 6-thioguanine on human hepatocytes

Cited by 70 publications

References 22 publications

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

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

Quinoline-based antimalarial hybrid compounds

Fabrication and evaluation of [Co(phen)2L]3+-modified DNA-MWCNT and SDS-MWCNT electrodes for electrochemical detection of 6-mercaptopurine

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