Attenuation of methotrexate induced hepatotoxicity by epigallocatechin 3-gallate

Abstract

Methotrexate (MTX) is currently used as first-line therapy for autoimmune diseases like rheumatoid arthritis, psoriasis, and systemic lupus erythematous. However, its use is limited by its hepatotoxic potential. Epigallocatechin-3-gallate (EGCG), an abundant catechin present in tea possesses potent antioxidant activity and effectively ameliorates oxidative stress-related disorders. This study aimed to investigate the hepatoprotective influence of EGCG in a MTX-induced rat model of hepatotoxicity. Sprague Dawley rats pretreated with EGCG (40 mg kg⁻¹ b.w., p.o.) were administered a single dose of MTX (20 mg kg⁻¹ b.w., i.p.) and its hepatoprotective efficacy compared with folic acid (1 mg kg⁻¹ b.w., i.p.). On day 10, blood samples were collected to determine plasma levels of aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH), while the livers were examined for histopathogical changes along with levels of oxidative stress measured in terms of myeloperoxidase (MPO) activity, protein carbonylation (PCO), lipid peroxidation (LPO), and activities of cellular enzymatic antioxidants – superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). MTX significantly increased the plasma levels of AST, ALT, ALP, and LDH, which were prevented by pretreatment with EGCG, and was corroborated by histopathology. Additionally, MTX-induced hepatic oxidative stress as measured by increased generation of MPO, enhanced PCO, LPO, and decreased activities of antioxidant enzymes was mitigated by pretreatment with EGCG. The amelioration of MTX-induced hepatotoxicity by EGCG endorsed the inclusion of an anti-oxidant during chronic administration of MTX.

Graphical Abstract

The study aimed to demonstrate the protective effect of epigallocatechin gallate (EGCG) against Methotrexate (MTX) induced hepatic injury via reduction of oxidative stress. Aspartate aminotransferase (AST), Alanine transaminase (ALT), Alkaline phosphatase (ALP), Lactate dehydrogenase (LDH), Myeloperoxidase (MPO), Malondialdehyde (MDA), Protein Carbonylation (PCO), Superoxide dismutase (SOD), Catalase (CAT), Glutathione Peroxidase (GPx).

Keywords:

• Anti-oxidant
• epigallocatechin-3-gallate (EGCG)
• hepatoprotective effect
• methotrexate
• rheumatoid arthritis
• tea

Disclosure statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Additional information

Funding

The work was supported by Fund for Improvement of S&T infrastructure in Universities and Higher Educational Institutions (FIST) Program, Department of Science & Technology, DST, Govt. of India, SR/FST/LS1-663/2016 and Department of Health Research, Govt. of India, ‘Establishment of Multidisciplinary Research Unit’ No.: V0.25011/103/2016-HR. MC is the recipient of a JC Bose Fellowship, SERB, Govt. of India, SSG and RS are recipients of a Senior Research Fellowship from CSIR (Council of Scientific and Industrial Research, Govt. of India) and ICMR (Indian Council of Medical Research, Govt. of India), respectively.