Protective role and molecular basis of N-acetyl-L-cysteine usage in azathioprine-induced rat hepatocyte necrosis

Menor, César; Cara, Carlos J.; Fernández‐Moreno, María Dolores; Fueyo, Jesús; Escribano, Óscar; Olleros, Tomás; Arriaza, Encarmacion; Lorusso, Michele; Paola, Mario Di; Domingo, Alberto; Guijarro, Luis

doi:10.1016/s0016-5085(03)83650-8

Cited by 1 publication

(1 citation statement)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The present findings suggest that macelignan could be used as a protective agent against various hepatotoxins such as cisplatin, acetaminophen, tamoxifen and azathioprine which are known to activate JNK. [47][48][49] Cisplatin has been shown to induce acute renal failure in mice and humans. 50) Further studies are necessary to confirm whether macelignan works in kidney or other tissues.…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Macelignan on Cisplatin-Induced Hepatotoxicity Is Associated with JNK Activation

Sohn

Han

Kim

et al. 2008

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

In the clinical field, the most important form of toxic hepatic injury is caused by therapeutic agents. Drug-induced liver injury is the most frequent reason for the withdrawal of an approved drug from the market, and it is also responsible for more than 50% of cases of acute liver failure in the United States.1) More than 600 drugs have been associated with hepatotoxicity, and there are now a number of reports that reactive metabolites formed from drugs such as acetaminophen, tamoxifen, diclofenac, and troglitazone are known to cause hepatotoxicity. 2)Cisplatin (cis-diamminedichloroplatinum [II]) is one of the most effective antineoplastic drugs, and it is particularly used for the treatment of ovarian, testicular and head and neck cancers. 3,4) In spite of its chemotherapeutic activity, various adverse effects, including renal dysfunction, nausea and vomiting, myelosuppression, ototoxicity, and nephrotoxicity, associated with its clinical use are well known. 5) Among them, nephrotoxicity is frequent and a major limitation to the use of this drug. Several mechanisms, including oxidative stress, inflammation, genotoxic damage, and cell cycle arrest, have been examined in cisplatin-induced nephrotoxicity. [6][7][8] However, cisplatin-induced liver toxicity and the mechanisms have been little studied, except for some clinical reports. 9-11)Myristica fragrans HOUTT. (Myristicaceae) is a perennial herb native to Indonesia and cultivated in South Africa, the Molucca Islands, India and other tropical areas. Its fruits, commonly known as mace (outer husk) or nutmeg (inner seed or kernel), has been used traditionally for spice and also possesses carminative, astringent, hypolipidaemic, antithrombotic, antiplatelet aggregation, antifungal, aphrodisiac, anxiogenic, antidiarrheal and anti-inflammatory activities.12-14) Macelignan (Fig. 1) isolated from M. fragrans has been reported to have antioxidant activity and cause alteration in hepatic enzyme activities, [15][16][17] however, the protective effect of macelignan against hepatotoxicity has not yet been examined.The objective of the current study was to examine the protective effects of macelignan on cisplatin-induced hepatotoxicity. For this purpose, we evaluated the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Several studies have reported that cisplatin activity is related to the cascades of mitogen-activated protein kinases (MAPKs) including c-Jun N-terminal kinases (JNKs, also referred to as stress-activated protein kinases, SAPK), extracellular signal-regulated kinases (EKRs), and p38 kinases. 18,19) Accordingly, we examined whether the protective activity of macelignan against cisplatin-induced hepatotoxicity is associated with the mitogen-activated protein kinase (MAPK) signaling pathway. (Fig. 1) was isolated from Myristica fragrans HOUTT. (Myristicaceae) as described previously. 20) Dried seed kernels (100 g) of Myristica fragrans were ground and extracted twice with 75% aqueous methanol (400 ml, v/v) for 24 h at room te...

show abstract