Methotrexate-induced Liver Toxicity Research Articles

Astaxanthin effect on apoptotic biomarkers in methotrexate-induced liver injury

Methotrexate is used in the treatment of cancer, psoriasis, rheumatoid arthritis and several other disorders. It has a hepatotoxic potential side effect. Patients who have no access to alternative medications face a serious
 
 challenge as a result. The current study aimed to assess the apoptotic potential of methotrexate on liver cells and evaluate the hepatoprotective activity of the potent antioxidant astaxanthin, by downregulation of apoptotic biomarkers caspase 9 and caspase 3.
 A model of methotrexate-induced liver toxicity was employed on male rats. Thirty-six rats were divided into six groups; a negative control group, methotrexate induction group given (20 mg/kg) on day 13, three groups pretreated with astaxanthin in ascending doses (50, 75 and 100 mg/kg) for 14 days before methotrexate, and a conventional therapy group pretreated with silymarin (200mg/kg).
 The use of methotrexate significantly increased liver tissue caspase 9 and caspase 3 compared to the negative control. On the other side, astaxanthin used in all three doses significantly normalized these biomarkers. This study revealed that since astaxanthin significantly decreased caspase 9 and caspase 3 that are involved in the apoptotic pathway, it could be used as pretreatment in patients treated with methotrexate to alleviate its hepatotoxicity.

Astaxanthin affects oxidative stress biomarkers in methotrexate-induced hepatotoxicity

Methotrexate is a chemotherapeutic and immunosuppressive drug used in the treatment of cancer, psoriasis, rheumatoid arthritis and several other disorders. Its use predisposes to hepatotoxicity which is a serious side effect. The current study aimed to assess the oxidative-stress-causing potential of methotrexate to liver cells and evaluate the hepatoprotective activity of the potent antioxidant astaxanthin, by affecting the oxidative stress biomarkers GSH (glutathione), SOD (superoxide dismutase), CAT (catalase) and MDA (malondialdehyde). A model of methotrexate-induced liver toxicity was employed on male rats. Thirty-six rats were divided into six groups; a negative control group, methotrexate induction group given (20 mg/kg) I.P. on day 13, three groups pretreated with oral astaxanthin in ascending doses (50, 75 and 100 mg/kg) for 14 days before methotrexate, and a conventional therapy group pretreated with silymarin (200mg/kg). The use of methotrexate significantly decreased liver tissue GSH, SOD and CAT while significantly increasing MDA, compared to the negative control. On the other side, astaxanthin used in all three doses significantly normalized these biomarkers. This study revealed that since astaxanthin significantly increased GSH, SOD and CAT while decreasing MDA that minimizes oxidative stress, it could be used as pretreatment in patients treated with methotrexate to decrease its hepatotoxicity.

The effect of complex herbal extract and methotrexate on suppressing adjuvant arthritis in rats

The present study evaluated the therapeutic benefits of complex herbal preparation named CBMDS, consisting of turmeric (Curcuma longa), Boswellia (Boswellia serrata), Methylsulphonylmethane, Devil’s Claw (Harpagophytum procumbens) and Silymarin, using it in combination with methotrexate, in order to suppress adjuvant arthritis in rats, and to attenuate methotrexate-induced liver damage. Adjuvant arthritis was induced in 28 rats by a single subplantar injection of complete Freund’s adjuvant (0.1 mL) into the left hind paw. The animals were divided into four groups (with seven animals in each). Group I received CBMDS, Group II - CBMDS in combination with methotrexate, and Group III just methotrexate. The treatment lasted from day 0 to day 17 (CBMDS was given daily except weekends in a dose of 160 mg/kg, methotrexate - 2 mg/kg once a week). Group IV was the control group. Clinical (body weight, hind paw volume, erythrocyte sedimentation rate, leukocyte count), biochemical (serum pro-/antioxidant activity markers), immunological (serum interleukin levels) and histological changes in joint and liver tissues were evaluated. CBMDS significantly alleviated arthritis and reduced hepatic damage, which was more evident in the methotrexate group. The combined treatment also markedly reduced arthritic symptoms and levels of malondialdehyde. Antioxidant activity was significantly higher in treated Groups I and II. CBMDS and its combination with methotrexate promoted anti-arthritic action, reduced histological changes in the joint tissues, and minimized methotrexate-induced liver toxicity.

Research progress on protective effect of traditional Chinese medicine and natural medicine on methotrexate-induced liver toxicity

Methotrexate(MTX) is a commonly used antimetabolite, which can be used in the treatment of a variety of diseases. However, hepatotoxicity in the use of MTX severely limits its clinical use. Therefore, how to prevent and treat hepatotoxicity of MTX has become an urgent clinical problem. This paper summarizes and analyzes relevant literatures on the prevention and treatment of hepa-totoxicity caused by MTX with traditional Chinese medicines and natural medicines in recent years. MTX-induced hepatotoxicity mechanisms include folate pathway, oxidative stress damage and adenosine pathway, of which oxidative stress theory is the main research direction. A total of 14 kinds of traditional Chinese medicine and natural medicine extracts including white peony root, and 21 kinds of natural monomer compounds, including berberine, play an anti-MTX-induced hepatotoxic effect by resisting oxidative stress, inhibiting inflammation and regulating signal pathways. According to current studies on the prevention and treatment of hepatotoxicity induced by MTX with traditional Chinese medicines and natural medicines, there are insufficiencies, such as partial and superficial mechanism studies, inadequate combination of experimental research and clinical practice, non-standard experimental design and lack of application of advanced technologies and methods. This paper systematically reviewed the effects and mechanisms of traditional Chinese medicines and natural medicines against hepatotoxicity induced by MTX and defined current studies and deficiencies, in the expectation of proposing new study strategies and directions and providing scientific basis for rational clinical use of MTX and development of new drugs against MTX hepatotoxicity.

Investigation of Protective Effect of Matricaria Chamomilla L. Extract on Methotrexate-Induced Hepatotoxicity in Wistar Rat

Methotrexate (MTX) was shown to cause oxidative stress and liver damage. The objective was to investigate the possible protective effects of Matricaria Chamomilla L. (chamomile) extract with anti-oxidant and anti-inflammatory properties on the methotrexate-induced liver toxicity. Twenty four Wistar rats were divided into four groups. MTX group was injected intraperitoneally on days 7 and 14 with 20 mg/kg methotrexate. Groups CE200 (chamomile extract 200 mg/kg/day) and CE300 (chamomile extract 300 mg/kg/day) received the same dose of methotrexate added with chamomile extract orally for 15 days at 200 mg/kg and 300 mg/kg respectively and the last group was healthy control group. Results of biochemical analyses indicated serum liver biomarkers (aminotransferases), alkaline phosphatase (ALP), albumin, and liver content of anti-oxidant enzymes (catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px)), reduced glutathione (GSH) and total anti-oxidant capacity (TAC) significantly increased (P <0.05-0.001) to normal in the CE treated groups compared to those of the MTX group. Serum bilirubin and hepatic malondialdehyde (MDA) levels significantly increased (P ˂0.001) in MTX group compared to those of the control group and decreased in CE200 and CE300 groups compared to those of the MTX group. Histopathological study showed inflammatory damage, necrotic cells and lipid infiltration in MTX group. In the groups treated with the chamomile extract, a significant improvement was observed in liver tissue in response to increased dose of the extract. In conclusion, chamomile extract administration could have a protective role in methotrexate-induced liver toxicity in rats through improving anti-oxidant defense system.

The impact of Crocus sativus stigma against methotrexate-induced liver toxicity in rats.

Background The adverse effects of methotrexate (MTX) mainly hepatotoxicity restrict its clinical use. This study was designed to investigate the protective effects of saffron (Crocus sativus) (CS) extract on MTX-induced hepatotoxicity. Methods Twenty-eight male Wistar rats randomly divided into four equal groups. Except for control, all groups received a single intraperitoneal (i.p.) injection of MTX on the 3rd day of study. The CS extract was given (80 mg/kg i.p.) to rats 3days before MTX and continued for the next 7days (Pre&Post-CS group) or administrated after MTX injection and lasted for 7days (Post-CS group). On the 11th day, all rats were sacrificed and their plasma levels of liver enzymes including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were determined. Also, liver histopathology and hepatic levels of malondialdehyde (MDA), nitric oxide (NO) and super oxidase dismutase (SOD) were evaluated. Results The results showed that MTX significantly incremented plasma levels of AST, ALT, ALP and LDH (all p<0.001) and hepatic MDA and NO levels; whereas, decreased SOD activity. Histological alterations such as early fatty changes were evident in the MTX group. Administration of CS extract at both methods could ameliorate liver enzyme elevation, oxidative/nitrosative stresses and morphological alterations of the liver. Pre-and-post treatment with CS extract showed better protective effects than only post-treatment. Conclusion The present findings provide showing CS could effectively alleviate MTX-induced hepatotoxicity in rats. Further investigations are recommended to determine the exact mechanisms underlying the hepatoprotective potential of saffron.

Hepatoprotective effect of rhein against methotrexate-induced liver toxicity

The purpose of this study was to investigate the protective effect of rhein, a major metabolite of diacerein, on methotrexate (MTX)-induced hepatotoxicity and clarify the pharmacological mechanism. Rhein significantly reduced the elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) caused by MTX in rat serum and improved liver morphological damage induced by MTX. Moreover, rhein increased the cell survival rate and reduced the number of apoptosis cells in MTX-treated normal human hepatocyte (L02 cells). Rhein treatment in rats up-regulated nuclear factor erythroid 2-related factor 2 (Nrf2), B-cell lymphoma-2 (Bcl-2), heme oxygenase 1 (HO-1) and glutamate-cysteine ligase catalytic subunit (GCLC), and down-regulated Bcl-2 associated x (Bax) in mRNA and protein levels. Furthermore, rhein treatment further decreased protein expression of nuclear factor-kappa B (NF-κB), tumor necrosis factor alpha (TNF-α) and cysteine aspartic acid specific protease 3 (Caspase-3), increased protein expression of B-cell lymphoma-extra large (Bcl-xl), and reduced mRNA expression of Bcl-2 homologous antagonist/killer (Bak) in MTX-treated rat liver in vivo. However, the protein expression changes of Nrf2, HO-1, GCLC, Bcl-2, Bcl-xl and Bax could be abrogated by Nrf2 antagonist brusatol. In addition, protective effect of rhein against MTX-mediated liver damage could also be suppressed by Nrf2 siRNA in L02 cells. Taken together, these findings suggested that rhein ameliorated liver damage mediated by MTX through acting on Nrf2-HO-1 pathway. NF-κB, TNF-α, Caspase-3 and Bcl-2 family were also participated in the protection. As effectively hepatoprotective ability of rhein, it would raise an important issue for patients orally receiving MTX treatment together with diacerein/rhein.

Hepatoprotective effect of berberine against methotrexate induced liver toxicity in rats

Hepatotoxicity is one of the major side effects of methotrexate (MTX), which restricts the clinical use of this drug. Berberine (BBR) is a natural compound with multiple pharmacological activities such as antioxidant, antiapoptotic and anti-inflammatory effects. In this study, the effect of BBR on MTX-induced hepatotoxicity was studied. A total number of 28 male Wistar rats were randomly divided into four experimental groups. Rats were pretreated with BBR orally with dose of 100mg/kg for 10 consecutive days and MTX (20mg/kg, intraperitoneally) was administrated on the 9th day. Then on day 11, blood samples were collected to determine serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The extracted livers were used for histological examination, biochemical assays and real time PCR studies. Malondialdehyde (MDA), glutathione (GSH), protein carbonyl (PC), nitric oxide (NO) levels, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and myeloperoxidase (MPO) activities were assessed in hepatic tissue. In addition, the expression of SOD and PGx was measured using real-time PCR method in hepatic tissue. Results showed that MTX administration significantly increases AST, ALT and ALP levels (all p<0.001). It also, increases MDA, PC, NO levels and MPO activity (p<0.001, p<0.01, p<0.05 and p<0.01 respectively). Moreover, MTX decreases hepatic GSH level, SOD, GPx and CAT activities (all p<0.001). Pre-treatment with BBR for 10days prevented some of these changes. Serum levels of AST and ALT decreased (all p<0.001). Hepatic MDA level decreased (p<0.001) and GSH level as well as GPx activity increased (p<0.05 and p<0.01 respectively). Our results indicated that BBR might be useful for prevention of the hepatotoxicity induced by MTX via ameliorative effects on biochemical and oxidative stress indices.

Protective effects of phloridzin against methotrexate-induced liver toxicity in rats

BackgroundLiver is the largest internal organ concerning with metabolism, hormonal balance and clarifying of the toxins. One of the main complications of methotrexate (MTX) therapy was the hepatic injury. ObjectiveThis study was conducted to elucidate the possible protective effects of phloridzin (PHL) against MTX-induced hepatotoxicity as compared to standard agent N-acetylcysteine (NAC). Materials and methodsRats were randomly divided into a normal control group, a respective group (PHL 40mg/kg/day orally (p.o.) for 10 consecutive days), a hepatotoxicity control group (MTX 20mg/kg, i.p., once), and three treated groups received NAC (150mg/kg/day; a reference standard), PHL (40mg/kg/day) and PHL (80mg/kg/day) p.o. for 10 consecutive days, at the end of the day 3 of the experiment rats were administered MTX. Assessed biomarkers included serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) as liver function parameters, serum tumor necrosis factor-α (TNF-α) and cyclooxygenase-II (COX-II), as inflammatory biomarkers, hepatic total antioxidant capacity (TAC), thiobarbituric acid reactive substances (TBARS), glutathione reduced (GSH), nitrite (NO2−), catalase (CAT), glutathione-S-transferase (GST) and superoxide dismutase (SOD) as oxidative stress biomarkers. Furthermore, hepatic caspase-3 expression was assessed. Biochemical and molecular estimations reinforced by histopathological findings. ResultsRats pre-treated with PHL significantly reduced hepatic injury, evidenced by significant reductions in ALT, AST and LDH, TNF-α and COX-II levels, significant reductions in hepatic NO2− and TBARS levels, and significant elevations in hepatic TAC, GSH, GST, CAT and SOD levels. Additionally, downregulation of hepatic caspase-3 expression. Finally, histopathological results consistent with our previous findings. ConclusionPHL protects against hepatic injury in rats mainly through mitigation of oxidative stress, inflammation and apoptosis in hepatic tissues and may be promising to alleviate and early treatment of MTX-induced hepatoxicity in man.

Melatonin-lycopene combination improves methotrexate-induced liver toxicity in rats via anti-inflammatory effect

Melatonin-lycopene combination improves methotrexate-induced liver toxicity in rats via anti-inflammatory effect

Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity.

Sitagliptin is selective dipeptidyl peptidase-4 inhibitor (DPP4-I), used clinically as a new oral anti-diabetic agent. This study explored the underlying mechanisms of the hepatoprotective role of sitagliptin pretreatment against methotrexate (MTX) induced hepatotoxicity in mice. Forty mice were divided into four groups (10 mice each); control, MTX, and two sitagliptin groups (pretreated with sitagliptin 10 and 20 mg/kg/day, respectively) for five consecutive days prior to MTX injection. Results showed that MTX induced marked hepatic injury in the form of cloudy swelling, hydropic degeneration, apoptosis and focal necrosis in all hepatic zones. Biochemical analysis revealed significant increase in the serum transaminases, alkaline phosphatase and lactate dehydrogenase in MTX group. Oxidative stress and depressed antioxidant system of the hepatic tissues were evident in MTX group. MTX down-regulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and reduced its binding capacity. Additionally, MTX increased the activation and the expression of nuclear factor kappa-B (NF-κB) and downstream inflammatory mediators. MTX induced the activation of inducible nitric oxide synthase (iNOS) and increased nitrite/nitrate level. Finally, hepatic cellular apoptosis was clearly obvious in MTX-intoxicated animals using TUNEL staining. Also, there was increase in the immunoexpression of pro-apoptotic protein Bax, increase in Bax and caspase-3 levels and decrease in the level of anti-apoptotic Bcl2 in liver. On the other hand, sitagliptin pretreatment significantly ameliorated all of the above mentioned biochemical, histopathological, immunohistochemical changes induced by MTX. These results provide new evidences that the hepatoprotective effect of sitagliptin is possibly mediated through modulation of Nrf2 and NF-κB signaling pathways with subsequent suppression of inflammatory and apoptotic processes.

Pre-administration of turmeric prevents methotrexate-induced liver toxicity and oxidative stress.

BackgroundMethotrexate (MTX) is an antimetabolite broadly used in treatment of cancer and autoimmune diseases. MTX-induced hepatotoxicity limits its application. We investigated hepatoprotective effects of turmeric in MTX-induced liver toxicity.MethodsAll experiments were performed on male Wistar albino rats that were randomly divided into six groups. Group one received saline orally for 30 days (control group), groups two and three received turmeric extract (100, 200 mg/kg respectively) orally for 30 days, group four received single dose, of MTX IP at day 30, groups five and six received turmeric extract 100 and 200 mg/kg orally respectively for 30 days and single dose of methoterxate IP (20 mg/kg) at day 30. Four days after MTX injection animals were sacrificed and evaluated. Blood ALT and AST (indicators of hepatocyte injury), ALP and bilirubin (markers of biliary function), albumin (reflect liver synthetic function) as well as the plasma TAS concentration (antioxidant defenses) were determined. The cellular antioxidant defense activities were examined in liver tissue samples using SOD, CAT, and GSH-Px for the oxidative stress, and MDA for lipid peroxidation. In addition, liver damage was evaluated histopathologically.ResultsMTX significantly induced liver damage (P < 0.05) and decreased its antioxidant capacity, while turmeric was hepatoprotective. Liver tissue microscopic evaluation showed that MTX treatment induced severe centrilobular and periportal degeneration, hyperemia of portal vein, increased artery inflammatory cells infiltration and necrosis, while all of histopathological changes were attenuated by turmeric (200 mg/kg).ConclusionTurmeric extract can successfully attenuate MTX-hepatotoxicity. The effect is partly mediated through extract’s antinflammatory activity.

P1132 : Regulation of oxidative stress and lipid peroxidation in methotrexate-induced liver toxicity by pretreatment with turmeric

P1132 : Regulation of oxidative stress and lipid peroxidation in methotrexate-induced liver toxicity by pretreatment with turmeric

Automatic identification of methotrexate-induced liver toxicity in patients with rheumatoid arthritis from the electronic medical record.

To improve the accuracy of mining structured and unstructured components of the electronic medical record (EMR) by adding temporal features to automatically identify patients with rheumatoid arthritis (RA) with methotrexate-induced liver transaminase abnormalities. Codified information and a string-matching algorithm were applied to a RA cohort of 5903 patients from Partners HealthCare to select 1130 patients with potential liver toxicity. Supervised machine learning was applied as our key method. For features, Apache clinical Text Analysis and Knowledge Extraction System (cTAKES) was used to extract standard vocabulary from relevant sections of the unstructured clinical narrative. Temporal features were further extracted to assess the temporal relevance of event mentions with regard to the date of transaminase abnormality. All features were encapsulated in a 3-month-long episode for classification. Results were summarized at patient level in a training set (N=480 patients) and evaluated against a test set (N=120 patients). The system achieved positive predictive value (PPV) 0.756, sensitivity 0.919, F1 score 0.829 on the test set, which was significantly better than the best baseline system (PPV 0.590, sensitivity 0.703, F1 score 0.642). Our innovations, which included framing the phenotype problem as an episode-level classification task, and adding temporal information, all proved highly effective. Automated methotrexate-induced liver toxicity phenotype discovery for patients with RA based on structured and unstructured information in the EMR shows accurate results. Our work demonstrates that adding temporal features significantly improved classification results.

Is There a Role for the MTHFR 677C&gt;T and 1298A&gt;C Polymorphisms in Methotrexate-Induced Liver Toxicity?

Methotrexate treatment Methotrexate (MTX) is an anti m etabolite used in the treatment of different types of cancer and in a number of autoimmune diseases, such as rheumatoid arthritis (RA). Interestingly, the dosage used to treat patients varies substantially for different types of diseases. Depending on the dosage given, several forms of toxicity can be expected (e.g., mucositis, bone marrow suppression or liver toxicity). These MTX-induced toxic effects can be reversed with the administration of leucovorin (5-formyltetrahydrofolate). This so-called leucovorin rescue is part of standard treatment when high doses of MTX are used, which is mostly the case in the treatment of cancer, and is also recommended in the treatment of autoimmune diseases, in which low doses of MTX are given. Particularly in cancer patients, MTX is given because of its ability to inhibit the folate pathway enzymes, including the enzymes DHFR and MTHFR. MTHFR, and especially the gene coding for the MTHFR enzyme, has been repeatedly studied regarding its relationship with toxicities caused by MTX and the genetic variants present in this gene. It has been suggested that genetic variants of the MTHFR gene are associated with MTX-induced liver toxicity, bone marrow suppression and the appearance of mucositis. The two most commonly studied genetic variants are the MTHFR 677C>T and 1298A>C polymorphisms. Both variants are known to result in lower enzyme activity, which is probably the underlying cause of MTX-related toxicity. Clinical relevance of the 677C>T & 1298A>C polymorphisms in MTX-induced liver toxicity Genetic association studies into the role of MTHFR in MTX-induced toxicities have mainly been performed in patients with RA and cancer; therefore, we will focus on these two diseases. There are several studies describing an association between the 677C>T genetic variant of the MTHFR gene and liver toxicity. However, there are also several studies demonstrating no association at all. Some of the main problems with these genetic studies are the number of

Practice gaps. Methotrexate-induced liver toxicity: replacing the liver biopsy.

Practice gaps. Methotrexate-induced liver toxicity: replacing the liver biopsy.

The role of the MTHFR 677C&gt;T polymorphism in methotrexate-induced liver toxicity: a meta-analysis in patients with cancer

Methotrexate (MTX), one of the important pillars in the treatment of different forms of cancer, is associated with the development of hepatotoxicity. The 677C>T variant (rs1801133) in the methylenetetrahydrofolate reductase (MTHFR) gene might affect the development of hepatotoxicity. Results in literature are, however, contradictive. The aim of this study was to evaluate the role of the MTHFR 677C>T polymorphism in MTX-induced hepatotoxicity by analyzing a Dutch cohort of pediatric patients treated with high doses of MTX and subsequently performing a meta-analysis. Ninety-eight patients receiving 542 courses of high-dose MTX were genotyped for the MTHFR 677C>T variant. Hepatotoxicity was evaluated retrospectively according to common terminology criteria for adverse events-National Cancer Institute criteria. The influence of MTHFR 677C>T on hepatotoxicity was examined using a generalized estimating equation (GEE) analysis. A fixed-effect meta-analysis based on this and previous studies investigating the association between the MTHFR 677C>T polymorphism and uniformly coded hepatotoxicity was performed. The GEE analysis showed an increased risk of developing hepatotoxicity for T versus C allele (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.0-3.2, P=0.04). This finding was not supported by the meta-analysis including seven studies and 1044 patients; the OR for the 677T versus C allele was 1.1 (95% CI 0.84-1.5, P=0.25). Heterogeneity between studies was observed, possibly related to differences in MTX dose and leucovorin rescue. In conclusion, in patients with cancer, the MTHFR 677T allele has only a minor role in the development of MTX-induced hepatotoxicity. Observed heterogeneity between studies warrants further study into (tailored) leucovorin rescue.

Role of Ursodeoxycholic Acid in Prevention of Methotrexate-induced Liver Toxicity

Methotrexate (MTX)-induced hepatotoxicity restricts the clinical use of this immunosuppressive drug. In this study, our aim was to research the role of oxidative stress in the hepatic toxicity of MTX and the protective effect of ursodeoxycholic acid (UDCA) in this setting. Wistar type rats (n = 32) were divided into four groups; group-1 as the MTX + UDCA, group-2 as the MTX, group-3 as the UDCA, group-4 as the saline-receiving groups. The MTX + UDCA and MTX groups of rats received 50 mg/kg of UDCA administered orally; whilst physiological saline was administered orally to the MTX and saline groups and continued for the next 6 days. On the second day of the study, the MTX + UDCA and MTX groups had a single intraperitoneal dose of MTX of 20 mg/kg. The UDCA and saline groups also received similar volumes of physiological saline intraperitoneally. On the sixth day, serum samples were collected and analyzed for ALT, alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (GGT) and homogenated liver tissues were examined for reactive oxygen metabolites (ROM); luminol, lucigenin, lipid peroxygenation product malondialdehyde (MDA) and glutathione (GSH) levels. In the MTX group, serum ALT, ALP, GGT and tissue ROM levels were higher and GSH level was lower. On the histopathological examination, hepatocellular necrosis was clearly more evident in the MTX group than the MTX + UDCA group. UDCA treatment protects against MTX-induced liver toxicity. Histopathologically hepatocyte necrosis can be prevented by UDCA treatment, indicating clearly the hepatoprotective effect of this agent on MTX-induced liver injury.

698 Role of ursodeoxycholic acid in the prevention of methotrexate induced liver toxicity

698 Role of ursodeoxycholic acid in the prevention of methotrexate induced liver toxicity