Abstract
PurposeMethotrexate (MTX) induces hepatotoxicity, limiting its clinical efficacy as a widely known chemotherapy drug. In the current study, we examined the protective effect of human placenta extract (HPE) against MTX-induced liver damage in rats, as well as its ability to regulate antioxidative and anti-inflammatory liver responses.MethodsMale rats were orally administered MTX at a daily dose of 5 mg/kg-body-weight in the presence or absence of HPE (10.08 mg/kg) for 2 weeks. We measured the biological effects of MTX and HPE on the levels of liver enzymes, lipid profile, lipid peroxidation, oxidative stress biomarkers, and cytokines [tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10)]. In addition, histological examination and histopathological scoring of liver tissues were performed.ResultsMTX-treated rats showed significantly increased (p < 0.001) liver enzyme levels for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, total cholesterol, and triglyceride levels. However, HPE supplementation in MTX-treated rats significantly decreased (p < 0.001) these elevated levels. HPE supplementation also significantly reduced the oxidative stress biomarker malondialdehyde (MDA), reversed the reduction in glutathione (GSH), and markedly increased the antioxidant enzyme activities of catalase (CAT) and superoxide dismutase (SOD) in the livers of MTX-treated rats. Furthermore, HPE supplementation significantly decreased the MTX-elevated levels of the pro-inflammatory cytokines TNF-α, IL-6, and IL-10. Histopathological examinations showed that MTX produced severe cellular damage and inflammatory lesions in liver tissues, while treatment with HPE improved hepatic histologic architecture.ConclusionHPE has the ability to ameliorate methotrexate-induced liver injury in rats by mechanisms that include boosting antioxidative responses and down-regulating MDA and pro-inflammatory cytokine production.
Highlights
Methotrexate (MTX), a dihydrofolate reductase inhibitor, is an anti-metabolite used as a chemotherapeutic agent against different types of malignancies [1,2,3]
Supplementation with both MTX and human placenta extract (HPE) resulted in a significant decrease in AST (59.75 ± 0.6), alanine transaminase (ALT) (52.55 ± 1.64), and alkaline phosphatase (ALP) (149.62 ± 1.05) levels relative to the MTX-treated group (p < 0.001), a significant increase (p < 0.05) was still recorded in comparison with the control group
Oxidative stress and lipid peroxidation mediated by oxygen free radicals have been considered as an important cause of MTX-induced neurotoxicity [8,9,10,11], hepatotoxicity
Summary
Methotrexate (MTX), a dihydrofolate reductase inhibitor, is an anti-metabolite used as a chemotherapeutic agent against different types of malignancies [1,2,3]. MTX is used to treat a variety of other diseases, including autoimmune. Many risk factors can increase the hepatotoxic effect of MTX, including age, duration of exposure to MTX and its cumulative dose, alcohol consumption, history of nonalcoholic steatohepatitis, diabetes, obesity, hepatitis B or C virus infection, and hepatotoxic drugs [17, 18]. Cancer Chemotherapy and Pharmacology (2021) 88:961–971 non-alcoholic fatty liver disease, in which hepatic steatosis is observed without heavy alcohol consumption [19], has been linked to MTX therapy [20, 21]. As a serious side effect even at low doses, MTX can lead to hepatic fibrosis and cirrhosis. Low-dose MTX use in psoriasis was found to have a 7% risk of cirrhosis development, and transaminase elevations up to three times normal were seen in 8% of the patients monitored [22]. Sakthiswary et al reported that the cumulative dose of MTX was found to have a significant positive correlation with the alanine transaminase (ALT) level [23]
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