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

Abstract

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...

Protective effect of L-carnitine against cisplatin-induced liver and kidney oxidant injury in rats

“…Previous studies have reported the role of reactive oxygen species (ROS) in mediating the kidney and liver toxicity of xenobiotics [32,33]. CDDP increases the intracellular production of oxygen and nitrogen species in the kidney and liver by increasing the activity of cytochrome P450 enzymes, NADPH oxidase, xanthine oxidase, and adenosine deaminase [34].…”

Macelignan Attenuates Activations of Mitogen-Activated Protein Kinases and Nuclear Factor kappa B Induced by Lipopolysaccharide in Microglial Cells

“…32,33) It is well known that PPARg agonists elicit anti-inflammatory and anti-amyloidogenic effects and that MAPK has emerged as a key factor in the regulation of Tau and b-amyloid precursor proteins. 10,34) This study explored possible anti-inflammatory mechanisms related to MAPKs by macelignan in LPS-stimulated BV-2 microglias cells.…”

<b>Biological Effects of Myristica fragrans</b>

“…These findings suggest that the hepatoprotective activity of myristicin may be, at least in part, due to the inhibition of TNF-alpha release from macrophages. Sohn et al (2008) observed that the hepatoprotective effects of macelignan, isolated from M. fragrans is related to activation of the mitogen activated protein kinase (MAPK) signaling pathway, especially JNK and c-Jun.…”