Modulation of Liver P-Glycoprotien Expression May Contribute to Gossypin Protection against Methotrexate-Induced Hepatotoxicity

Mohamed, Mervat Z.; Sheikh, Azza Kamal El; Mohammed, Hanaa H.

doi:10.4103/ijp.ijp_824_19

Cited by 8 publications

(5 citation statements)

References 27 publications

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“…P-gp and Mrp-2 are efflux transporters that decrease the intracellular accumulation of a drug or a toxicant in several organs, including the liver [ 12 , 37 ]. The current results show that MTX significantly reduced the hepatic expression of P-gp and Mrp-2, which agrees with previous studies [ 37 , 38 ]. Therefore, the paeonol-induced increase in the expression of P-gp and Mrp-2 proteins provides a plausible explanation for its hepatoprotective effects against MTX-induced injury by increasing its efflux.…”

Section: Discussionsupporting

confidence: 94%

Paeonol Protects against Methotrexate Hepatotoxicity by Repressing Oxidative Stress, Inflammation, and Apoptosis—The Role of Drug Efflux Transporters

et al. 2022

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Methotrexate (MTX) is an effective chemotherapeutic agent against a wide range of tumors and autoimmune diseases; however, hepatotoxicity limits its clinical use. Oxidative stress and inflammation have been implicated in the pathogenesis of MTX-induced hepatotoxicity. Paeonol is a natural phenolic compound reported for its antioxidant and anti-inflammatory properties. The current study aimed to investigate the protective effect of paeonol against MTX-induced hepatotoxicity in rats and various mechanisms that underlie this postulated effect. Paeonol was administered orally in a dose of 100 mg/kg, alone or along with MTX, for 10 days. Hepatotoxicity was induced via a single intraperitoneal dose of MTX (20 mg/kg) on day 5 of the experiment. Concomitant administration of paeonol with MTX significantly ameliorated distorted hepatic function and histological structure, restored hepatic oxidative stress parameters (MDA, NO, and SOD), and combated inflammatory response (iNOS and TNF-α). Additionally, paeonol enhanced cell proliferation and survival, evidenced by upregulating the proliferating cell nuclear antigen (PCNA) and suppressing apoptosis and the disposition of collagen fibers in rat livers treated with MTX. Importantly, paeonol upregulated the drug efflux transporters, namely P-glycoprotein (P-gp) and the multidrug resistance-associated protein 2 (Mrp-2) in MTX-treated rats. In conclusion, paeonol offered a potent protective effect against MTX-induced hepatotoxicity through suppressing oxidative stress, inflammation, fibrosis, and apoptosis pathways, along with P-gp and Mrp-2 upregulation.

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Section: Discussionsupporting

confidence: 94%

Paeonol Protects against Methotrexate Hepatotoxicity by Repressing Oxidative Stress, Inflammation, and Apoptosis—The Role of Drug Efflux Transporters

et al. 2022

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“…Additionally, the MTX-induced lung inflammation and fibrosis were revealed by a manifest escalation in the lung TNF-α, IL-8, TGF-β, and collagen contents. The significant elevation of inflammatory markers in addition to collagen as a fibrotic marker during MTX treatment was in harmony with Yamagami et al ( 2020 ); Mohamed et al ( 2021 ); Taskin et al ( 2021 ) and Zaki et al ( 2021 ). These actions could be attributed to the MTX’s ability to activate the leukocytes to increase the liberation of cytokines, which have a fundamental role in lung fibrosis formation through the epithelial-mesenchymal transition process and stimulation of NF-kβ and activator platelet-1 through ROS generation (Al Kury et al 2020 ).…”

Section: Discussionsupporting

confidence: 79%

Cinnamic acid mitigates methotrexate-induced lung fibrosis in rats: comparative study with pirfenidone

Abdalhameid,

Abd El-Haleim,

Abdelsalam

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Purpose Lung fibrosis is a heterogeneous lung condition characterized by excessive accumulation of scarred tissue, leading to lung architecture destruction and restricted ventilation. The current work was conducted to examine the probable shielding influence of cinnamic acid against lung fibrosis induced by methotrexate. Methods Rats were pre-treated with oral administration of cinnamic acid (50 mg/kg/day) for 14 days, whereas methotrexate (14 mg/kg) was orally given on the 5th and 12th days of the experiment. Pirfenidone (50 mg/kg/day) was used as a standard drug. At the end of the experiment, oxidative parameters (malondialdehyde, myeloperoxidase, nitric oxide, and total glutathione) and inflammatory mediators (tumor necrosis factor-α and interleukin-8), as well as transforming growth factor-β and collagen content, as fibrosis indicators, were measured in lung tissue. Results Our results revealed that cinnamic acid, as pirfenidone, effectively prevented the methotrexate-induced overt histopathological damage. This was associated with parallel improvements in oxidative, inflammatory, and fibrotic parameters measured. The outcomes of cinnamic acid administration were more or less the same as those of pirfenidone. In conclusion, pre-treatment with cinnamic acid protects against methotrexate-induced fibrosis, making it a promising prophylactic adjuvant therapy to methotrexate and protecting against its possible induction of lung fibrosis.

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“…It is possible that such upregulation is a feedback protective mechanism, by which the kidney can increase the elimination of the compound assaulting it. Previous studies reported controversial results regarding the effect of MTX on P-gp expression as MTX downregulated P-gp in the liver (Mohamed et al, 2021), while upregulating it in fibroblast-like synoviocytes of rheumatoid arthritis patients (Qin et al, 2018), and it had no effect on the testis (Morsy et al, 2020a). These results may suggest that the MTX effect on P-gp expression is organ-specific.…”

Section: Discussionmentioning

confidence: 96%

Paeonol Protects Against Methotrexate-Induced Nephrotoxicity via Upregulation of P-gp Expression and Inhibition of TLR4/NF-κB Pathway

et al. 2022

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Methotrexate (MTX) is a well-known anticancer drug that causes nephrotoxicity as a side effect. To investigate the mechanisms by which paeonol, a natural phenolic compound, can protect against MTX-induced nephrotoxicity, paeonol (100 mg/kg/day orally) was given to rats for 10 days, with or without MTX (20 mg/kg once i.p. at day 5). Compared to control, MTX caused nephrotoxic effects manifested by increased serum urea and creatinine and distortion in renal histological architecture, with a significant increase in the mean glomerular diameter and upregulation of kidney injury molecule-1. MTX caused oxidative stress manifested by decreasing reduced glutathione and superoxide dismutase while increasing malondialdehyde and nitric oxide. MTX also induced renal inflammation by upregulating TLR4, NF-κB, and IL-1β and caused apoptosis by induction of caspase 3. Administering paeonol with MTX improved kidney functional and structural parameters, as well as all oxidative, inflammatory, and apoptotic markers tested. Interestingly, both MTX and paeonol increased the expression of the renal efflux transporter P-glycoprotein (P-gp) that helps in MTX elimination, and their drug combination further upregulated renal P-gp. In silico, paeonol was neither a substrate nor an inhibitor of P-gp, suggesting that its effect on P-gp is not on functional but on the expression level. In vitro, paeonol and MTX were administered to colon cancer cells and their combination caused a progressive cellular cytotoxic effect, which was dose-dependent with the increase of paeonol concentration. In conclusion, paeonol protects against MTX-induced nephrotoxicity through antioxidant, anti-inflammatory, and antiapoptotic mechanisms and might potentiate MTX chemotherapeutic efficacy.

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Modulation of Liver P-Glycoprotien Expression May Contribute to Gossypin Protection against Methotrexate-Induced Hepatotoxicity

Cited by 8 publications

References 27 publications

Paeonol Protects against Methotrexate Hepatotoxicity by Repressing Oxidative Stress, Inflammation, and Apoptosis—The Role of Drug Efflux Transporters

Paeonol Protects against Methotrexate Hepatotoxicity by Repressing Oxidative Stress, Inflammation, and Apoptosis—The Role of Drug Efflux Transporters

Cinnamic acid mitigates methotrexate-induced lung fibrosis in rats: comparative study with pirfenidone

Paeonol Protects Against Methotrexate-Induced Nephrotoxicity via Upregulation of P-gp Expression and Inhibition of TLR4/NF-κB Pathway

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