Induced liver injury: A complete reviewRaghad D. Alamri a, 1, Mazen A. Elmeligy b, 1,

Induced liver injury: A complete reviewRaghad D. Alamri a, 1, Mazen A. Elmeligy b, 1, Ghadeer A. Albalawi a, 1, Sarah M. Alquayr a, 1, Samaher S. Alsubhi a, 1, Sabah H. El-Ghaiesh c, d, a cFaculty of Medicine, University of Tabuk, Tabuk 47713, Saudi Arabia Faculty of Medicine, Cairo University, Cairo 11562, Egypt Deaprtment of Pharmacology, Faculty of Medicine, Tanta University, Tanta 31527, Egypt d Department of Pharmacology, Faculty of Medicine, University of Tabuk, Tabuk 47713, Saudi ArabiabA R T I C L E I N F OKeywords: Leflunomide Immunomodulator Anti-inflammatory Antineoplastic Antiviral Drug-induced liver injury COVID-A B S T R A C TLeflunomide (LF) represents the prototype member of dihydroorotate dehydrogenase (DHODH) enzyme inhibitors. DHODH can be a mitochondrial inner membrane enzyme responsible for catalytic conversion of dihydroorotate into orotate, a rate-limiting step inside the de novo synthesis in the pyrimidine nucleotides. LF produces Brd Inhibitor Formulation cellular depletion of pyrimidine nucleotides necessary for cell development and proliferation. Depending on the impacted cells the outcome may be attainable as immunosuppression, antiproliferative, and/or the lately gained focus on the antiviral potentials of LF and its new congeners. Also, protein tyrosine kinase inhibition is definitely an extra mechanistic benefit of LF, which inhibits immunological events for instance cellular expansion and immunoglobulin production with an enhanced release of immunosuppressant cytokines. LF is authorized for the therapy of autoimmune arthritis of rheumatoid and psoriatic pathogenesis. Also, LF has been utilised off-label for the remedy of relapsing-remitting multiple sclerosis. Having said that, LF antiviral activity is repurposed and below investigation with associated compounds below a phase-I trial as a SARS CoV-2 antiviral in instances with COVID-19. Regardless of success in improving patients’ mobility and decreasing joint destruction, reported events of LF-induced liver injury necessitated regulatory precautions. LF really should not be utilized in patients with hepatic impairment or in mixture with drugs elaborating a burden on the liver without having normal monitoring of liver enzymes and serum bilirubin as security biomarkers. This study aims to evaluation the pharmacological and security profile of LF using a focus on the LF-induced hepatic injury in the viewpoint of pathophysiology and feasible protective agents.1. Introduction Leflunomide (LF) is definitely an immunomodulator and also a member in the disease-modifying antirheumatic family members of drugs (DMARDs). LF is utilized successfully in solo or as combined therapy in autoimmune arthritis [1]. Simple research reported immunosuppressant, antirheumatic,antineoplastic, and antiviral potentials of LF [2]. While clinical research secured an antirheumatic approval of LF in autoimmune arthritis, further research on antineoplastic effectiveness have so far been inconclusive [7]. Additionally, clinical CCR4 Antagonist drug studies around the benefit of LF in treating refractory viral infections including cytomegalovirus [10] and BK polyomavirus [114] have also been undertaken with out yielding aAbbreviations: TAK1, transforming development element -activated kinase 1; AMPK, adenosine monophosphate-activated protein kinase; ULK1, Unc-51-like autophagy activating kinase; PIM1 kinase, proto-oncogene serine/threonine protein kinase Pim-1; P56Lck, T-lymphocyte-specific protein tyrosine kinase; sEphrin-A1, soluble ephrin-A1; Eph-A2, ephrin-A2; JNK, c-Jun N-terminal kinases; LDH, lactate dehydrogenase; ERK1/2, extracel.