Background: Methotrexate is a folic acid antagonists that inhibits dihydrofolate reductase, resulting in a block in the synthesis of thymidine and inhibition of DNA synthesis. Methotrexate has been used for the treatment of malignancy, rheumatic disorders, and psoriasis and termination of intrauterine pregnancy. Recently, methotrexate has become a standard treatment for ectopic pregnancy. However, the use of methotrexate is limited due to high incidence of serious dose-dependent toxicity of methotrexate, including hepatotoxicity, renal damage, bone marrow suppression and gastrointestinal mucosal inflammation. Objective: Evaluate the effect of the treatment with multiple doses of methotrexate in the livers of mice. Materials &Methods: A total of (70) white mice at the ages of (4-8 weeks) and body weight of about (25+ 2 gm) were used in the study. Mice were divided into seven groups where each group received multiple doses of (0.05 mg/Kg) of methotrexate during an interval of six weeks where the animals of each group had injected with a single dose of (0.05 mg/Kg) of methotrexate at the beginning of each week and then, they were killed and autopsied after five days. On the other hand, the control group had received (0.1 ml) of normal saline. Liver slide sections were examined by light microscope and photographed. Then, images were assessed histopathologically and comparisons were made between mice groups received different doses of methotrexate.

Results: Results showed that, a single dose of (0.05 mg/kg) of methotrexate produced no liver tissue histopathological effects on the liver of the treated mice. While, six weeks of methotrexate treatment produced significant changes in the liver of the treated mice including lymphocyte infiltration, necrosis, liver tissue fatty degeneration and congestion and dalitation of the hepatic vein. Conclusions: It was concluded that, a single dose of (0.05 mg/Kg) of methotrexate had no effect on mice liver histology. While, multiple doses of methotrexate were associated with significant side effects included a hallmark of cellular infiltration and lesions of necrotic hepatocytes with congestion and dalitation of hepatic vein. Thus, the administration of multiple doses of methotrexate for the treatment of various medical conditions should be considered carefully to avoid liver damage of the patient especially in the case of ectopic pregnancy.