A Review on Hepatotoxic Effects of Methotrexate Therapy with Possible Strategies that May Counteract Hepatotoxicity

ABSTRACT


INTRODUCTION
Methotrexate inhibitor for dihydrofolate reductase, is an antimetabolite applied as a chemotherapy for many kinds of tumors 1 . Methotrexate involved in treatment of other disease involving diseases of autoimmunity, like psoriasis, rheumatism, vasculitis and ulcerative colitis and Crohn's disease (2)(3)(4)(5) . However, Methotrexate may cause neurotoxicity 6 , nephrotoxicity 7 , and hepatotoxicity (8,9) , Methotrexate have been linked to increase risk of liver damage, fibrosis and cirrhotic damage. Methotrexate work as a dihydrofolate analog which binds to the dihydrofolate reductase enzyme by preventing the production of tetrahydrofolic acid, that essential for production of DNA. Many factors that may increase risk of methotrexate induced hepatotoxicity, involving alcohol consumption, aging, timing for doses with Methotrexate and its amount of drug consumed by patient, medical history for liver disease, obesity, diabetic desease, hepatitis B or C virus infection and taking medicine associated with liver injury 8 . Moreover, non-alcoholic fatty injury, were liver steatosis is detected without heavy alcohol consumption 10 which has been similarly associated with Methotrexate therapy 11 . As dangerous adverse effects also low doses, Methotrexate may cause liver fibrotic damage and even cirrhosis. Minimum Methotrexate doses in chronic plaque psoriatic lesion was detected to have a 7% increase risk for development of cirrhotic liver injury , and aminotransferase rises up to triple times than standard level that found in 8% of the patients examined 13 . The incidence of Methotrexate -induced hepatic fibrosis and cirrhosis 14 .

Vitamin B12
This Vitamin is an vital vitamin that possess essential function in numerous activities in the human organ, involving DNA methylation and DNA biosynthesis, production of erythrocytes, with neuronal function 15 . Vitamin B12 belong to cobalamins compounds, mainly stored in the hepatic tissue, many studies have shown that vitaminB12 protect against numerous liver diseases such as acute hepatitis, cirrhosis 16 . Derya et al investigate the protective activity of vitamin B12 on the necrosis induced by methotrexate, a antagonist for folic acid. Vit B12 showed supplied experimental group appear improvement in all of the negative laboratory liver enzyme and histological finding. Therefore, Vitamin B12 is an essential supplement that applied for necrosis in tissue after methotrexate hepatotoxicity 17 .

Vitamin E:
is a type of lipid-soluble vitamin, and found as eight different forms, were tocopherol is the main active form . vitamin E is very important physiological antioxidant, tocopherol also proposed to have the main cellular binding antioxidant utilized via human tissue 18 . Vitamin E consider the main protection to prevent peroxidation of cellular membrane that essential for the cellular immunity. Vitamin E has been approved to reduce and mange hepatic inflammatory response and tissue fibrosis through modulating inflammation and signaling cascade by reducing the production of interleukin-6, tumor growth factor-β1, tumor necrosis factor-α, and further inflammation cytokines 19 . On other hand Binit et al show in his study prophylactic doses with vitamin E had preventive potential against hepatotoxicity induced by methotrexate in this experimental research showed that vitE in combination with folic acid superior to folic acid alone therefore the study results seem to be effective in ameliorating the hepatotoxicity of methotrexate therefore assists to fix the therapeutic dosing in patients 20 .

N-acetylcysteine:
is a classical antioxidant, usually included in experimental research and a celluar protective agent which effective for drug-induced hepatotoxicity. In the lab study, displayed that N-acetylcysteine maintain the hepatocyte from oxidation by preventing the production of peroxide free radical. Nacetylcysteine may also display its antioxidant effects on hepatocytes by preventing expression of adhesive materials, decreasing inflammatory cytokines and reduction-oxidation system inside cellular cytoplasm. However, Tuba et al reveal in his study that there is a valuable preventive effect of Nacetylcysteine against methotrexate-induced hepatic damage. The ameliorated action of N-acetylcysteine based on its potency to improve antioxidant cellular mechanism, and its capability to decrease inflammatory and apoptotic molecular cascade 21 .

3-Melatonin (N-acetyl-5-methoxytryptamine):
Ayat et al 22 concluded in her study that melatonin is promising in the protecting liver tissue from methotrexate toxic effect by their radical scavenging activities and antioxidant 22 . Melatonin is produced mainly through the pineal gland and is suggested to have antioxidant and defensive potential in opposit to oxidative stress 23 . It has potent antioxidant action thus safing cellular tissue against oxidative stress of DNA molecule, proteins, and lipids that involved in disease pathogenic pathway 24,25 . Melatonin maintains the hepatocyte from oxidative stress induced by pathological hypoxia formation 26 . Since melatonin has potent antioxidative potential, therefore melatonin has the ability to prevent the patients against MTX induced hepatotoxicity.

Erdosteine
: is a mucolytic agent that applied for the management of subacute lung disorder to improve bronchial clearance 27 . currently, a many experimental studies has emphasized the antioxidant potential of erdosteine, also to its approved mucolytic action 28 . however, erdosteine prevent oxidative tissue damage in many laboratory models studies that induced tissue damage by injecting animal with hepatotoxic drug 29 . study finding display that use of erdosteine in animal result improvement in liver damage by oxidation , inflammation, programed cell death, and pathological change, in comparison with methotrexate treated animal 30 .

Inulin (IN)
: a plant fructan-type polysaccharide, is commonly present naturally. The main wild sources of Inulin involve dahlia, chicory. Studies have establish that Inulin broad spectrum of biological activities, e.g. as a probiotic to enhance the intestinal flora environment, controlling glucose level, controlling cholesterol profile, antioxidant, antitumor, immunomodulatory action and new study show that Inulin with antioxidant action has hepatoprotective effects that mediated by the regulation of apoptosis and oxidative damage 31 .
6. Ferulic acid: as a polyphenolic drug, is produced through tyrosine and phenylalanine metabolic pathway and is mainly present in rice, barely, wheat, banana, tomato, citrus fruits and vegetables 32 . Ferulic acid established to be a potent cellular protective against oxidative stress, also effective for dermatological malignancy, viral infection, atrophy of muscular tissues, and fatigue 33 .On other hand Ferulic acid show many therapeutic actions, including anti-nociceptive, anti-inflammatory, anti-tumor, hypoglycemic, hypolipidemic, neuroprotection and hypotensive action 34 . Ferulic acid, possess polyphenolic nucleus with long side chain , which produce stabilization against phenoxy radicals, that are function as free radical scavenger ability 35 .However, Mozhdeh R et al found Ferulic acid in 100 mg/kg dose could can reduce oxidative damage, inflammatory response and enhance the internal cellular defense against oxidation by methotrexate. So Ferulic acid would be a good treatment to inhibit methotrexate associated hepatotoxicity 36 .

Human Placental Extract:
It has approved that maternal placental supply is the major organ of a huge number of biological effective growth factors 37 .like transforming growth factor-a (TGF-a) 38 , hepatocyte growth factor (HGF) and epidermal growth factor (EGF) 39 . Human placental extract also has Tryptophan as a major antioxidant content 40 . also, Human placental extract applied for numerous useful pharmacological indications, involving healing of wound 40 . Human placental extract was mentioned to improve hepatic regeneration after induction liver injury 41 and to inflammatory damage with apoptotic damage 42 . Mamdooh G approved in his study that Human placental extract will prevent methyotrexate induced hepatotoxicity in animals. Human placental extract show ability to improve and protect liver tissue against hepatotoxic agent by enhancing The endogenous antioxidant liver markers with reduction lipid peroxidation, with anti-inflammatory action.