Busting the myth of methotrexate chronic hepatotoxicity

Martino, Vincent Di; Weil, Delphine; Verhoeven, Frank; Aubin, F.; Avouac, Jérôme; Vuitton, Lucine; Lioté, Frédéric; Thévenot, Thierry; Wendling, Daniel

doi:10.1038/s41584-022-00883-4

Cited by 27 publications

(16 citation statements)

References 150 publications

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“…Hepatotoxicity indicates compound-driven liver damage. If the result predicts is positive (yes) therefore the compound causes acute and chronic liver disease [48]. Compound 7c has hepatotoxicity and causes liver disease but compound 11a is safe and not has hepatotoxicity.…”

Section: In Silico Toxicity Predictionmentioning

confidence: 99%

Synthesis, In Vitro Biological Investigation, and In Silico Analysis of Pyrazole-Based Derivatives as Multi-target Agents

Hassan

Aboulthana

2023

Egypt. J. Chem.

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The diseases-related complications and causes are threaded. Accordingly, the preparation of one drug with multiple targets is very pressing. In this context, the three series of pyrazole-based derivatives 7a-c, 9a-c, and 11a-c were designed and synthesized by using 5-amino-pyrazoles 3a-c as starting materials. The structures of various products 7a-c, 9a-c, and 11a-c were characterized by using various devices (elemental analysis and spectral tools). The biological activities of pyrazolebased products 7a-c, 9a-c, and 11a-c were estimated as antioxidant, anti-diabetic, anti-Alzheimer, and anti-arthritic. The estimation results showed that the two products 7c and 11a displayed powerful biological activities. In silico analysis (physicochemical, drug-likeness, and toxicity properties) of the two products 7c and 11a was performed. This research could be valuable for the exploration of one drug with multiple targets.

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Section: In Silico Toxicity Predictionmentioning

confidence: 99%

Synthesis, In Vitro Biological Investigation, and In Silico Analysis of Pyrazole-Based Derivatives as Multi-target Agents

Hassan

Aboulthana

2023

Egypt. J. Chem.

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“…MTX uses a number of cellular pathways to project its actions [ 12 ]. Nevertheless, hepatotoxicity has been associated with the prolonged administration of this agent [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Silibinin’s Effects against Methotrexate-Induced Hepatotoxicity in Adjuvant-Induced Arthritis Rat Model

Khawaja,

El-Orfali

2024

Pharmaceuticals

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Methotrexate (MTX) is the first drug of choice to treat several diseases, including rheumatoid arthritis. However, its administration is accompanied by severe side effects, most commonly hepatotoxicity. Hence, alternative therapies with a lower toxicity and fewer side effects are needed. This study aimed to investigate the antioxidant and hepatoprotective effects of silibinin (SIL, natural agent) against MTX-induced hepatotoxicity in an adjuvant-induced arthritis (AIA) rat model. Arthritic rats were treated with SIL (100 mg/kg) and/or methotrexate (2 mg/kg). Non-arthritic rats, arthritic untreated rats, and arthritic rats who received the vehicle were followed in parallel. SIL alleviated the systemic consequences of arthritis by restoring lost weight, decreasing the erythrocyte sedimentation rate, and ameliorating joint damage, which was evident both micro- and macroscopically. Additionally, SIL prevented the histopathological alterations in the liver and significantly reduced the liver damage caused by MTX and AIA, as shown by a decrease in the markers of liver damage (ALT and AST). Furthermore, SIL relieved the oxidative stress induced by AIA and MTX in liver tissue by decreasing the lipid peroxidation (MDA) levels and enhancing the antioxidant defense system (GSH levels; catalase and superoxide dismutase (SOD) activities). In conclusion, our results suggest that SIL is a potent antioxidant and hepatoprotective agent in arthritic rats. It markedly attenuated the progression and severity of the arthritic disease and eased the oxidative stress in liver tissue by improving the pro-oxidant/antioxidant balance.

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“…Methotrexate (MTX) has traditionally been used as the first-line drug due to its ease of administration, low cost, and availability [4]. However, its use is limited by the risk of myelosuppression and hepatotoxicity [5][6][7] and the uncertainty of its efficacy [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Unlocking the role of the B7‐H4 polymorphism in psoriasis: Insights into methotrexate treatment outcomes: A prospective cohort study

Wang,

Yang

et al. 2023

Immunology

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B7‐H4 is a recently discovered member of B7 family that negatively regulates T‐cell immunity, specifically Th1 and Th17 cell responses. However, its role in the pathogenesis of psoriasis has yet to be determined. This study aims to investigate the effect of B7‐H4 polymorphism on the efficacy of methotrexate (MTX) and its mechanism in psoriasis. Four single nucleotide polymorphisms of B7‐H4 were genotyped in 310 psoriatic patients who received 12‐week MTX. The protein expression of B7‐H4 in platelets was characterized using immunofluorescence staining, confocal laser scanning microscopy, and flow cytometry techniques. We found that GG genotype carriers of B7‐H4 rs1935780 had a lower Psoriasis Area and Severity Index (PASI) 75 response rate and higher weight (p = 0.0245) and body mass index (p = 0.0185) than AA and AG genotype carriers. Multiple regression analysis showed that the PASI score at baseline (p = 0.01) and age at disease onset (p = 0.003) were positively correlated with PASI 75 response rate, while weight (p = 0.005) and the rs1935780 genotype (p = 0.003) were negatively associated with PASI 75 response rate. B7‐H4 was expressed in the platelet plasma membrane and cytoplasm. Furthermore, the expression of B7‐H4 protein in platelets was lower in good responders than in non‐responders and was upregulated considerably after 12‐week MTX or in vitro MTX stimulation in good responders. Collectively, these results demonstrate that psoriatic patients with GG genotype of B7‐H4 rs1935780 had a poorer response to MTX. Low expression of B7‐H4 protein in platelets correlated with better clinical outcomes of MTX in psoriasis.

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Busting the myth of methotrexate chronic hepatotoxicity

Cited by 27 publications

References 150 publications

Synthesis, In Vitro Biological Investigation, and In Silico Analysis of Pyrazole-Based Derivatives as Multi-target Agents

Synthesis, In Vitro Biological Investigation, and In Silico Analysis of Pyrazole-Based Derivatives as Multi-target Agents

Silibinin’s Effects against Methotrexate-Induced Hepatotoxicity in Adjuvant-Induced Arthritis Rat Model

Unlocking the role of the B7‐H4 polymorphism in psoriasis: Insights into methotrexate treatment outcomes: A prospective cohort study

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