Metformin Protects Against Carbon Tetrachloride Hepatotoxicity in Mice

Poon, Michel Kwong Tat; Chiu, Po Yee; Mak, Duncan H.; Ko, Kam Ming

doi:10.1254/jphs.93.501

Cited by 25 publications

(23 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Metformin is known to protect liver against injury induced by various drugs such as carbon tetrachloride (14), methotrexate (15), and acetaminophen (16). It has been demonstrated that HMGB1 released from necrotic hepatocytes plays a critical role in the acetaminophen-induced liver injury model by accelerating the primary injury (26) as the liver injury is drastically reduced in hepatocyte-specific HMGB1 knock out mice (36) or by administration of anti-HMGB1-neutralizing antibody (41).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, metformin has hepatoprotective effects; it improves non-alcoholic steatohepatitis in humans (12) and prevents alcohol- and drug-induced liver injury in mice (13–16). Because inflammation is a major contributor to these diseases (17), metformin could protect these diseases at least through its anti-inflammatory function (4–6, 18, 19).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity

Horiuchi

Sakata

Narumi

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Metformin is the first-line drug in the treatment of type 2 diabetes. In addition to its hypoglycemic effect, metformin has an anti-inflammatory function, but the precise mechanism promoting this activity remains unclear. High mobility group box 1 (HMGB1) is an alarmin that is released from necrotic cells and induces inflammatory responses by its cytokine-like activity and is, therefore, a target of anti-inflammatory therapies. Here we identified HMGB1 as a novel metformin-binding protein by affinity purification using a biotinylated metformin analogue. Metformin directly bound to the C-terminal acidic tail of HMGB1. Both in vitro and in vivo, metformin inhibited inflammatory responses induced by full-length HMGB1 but not by HMGB1 lacking the acidic tail. In an acetaminophen-induced acute liver injury model in which HMGB1 released from injured cells exacerbates the initial injury, metformin effectively reduced liver injury and had no additional inhibitory effects when the extracellular HMGB1 was blocked by anti-HMGB1-neutralizing antibody. In summary, we report for the first time that metformin suppresses inflammation by inhibiting the extracellular activity of HMGB1. Because HMGB1 plays a major role in inflammation, our results suggest possible new ways to manage HMGB1-induced inflammation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity

Horiuchi

Sakata

Narumi

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…A 500 mg tablet was dissolved in DW, and the drug was given to the rabbits according to body weight once daily through a stomach tube. [1819]…”

Section: Methodsmentioning

confidence: 99%

Metformin ameliorates methotrexate-induced hepatotoxicity

Hadi

Al-Amran

Swadi

2012

Journal of Pharmacology and Pharmacotherapeutics

View full text Add to dashboard Cite

Objective:To study the effect of metformin on amelioration of hepatotoxicity induced by methotrexate.Materials and Methods:After a 2-weeks of acclimatization period, the animals were randomly separated into three groups (seven rabbits each), all groups were maintained on standard chow diet throughout the experiment (8 weeks). Group 1 was treated with normal saline water (control), Group 2 with methotrexate (MTX, hepatotoxic), and Group 3 with MTX plus metformin. Induction of hepatotoxicity was carried out by administration of MTX to the rabbit in a dose of 0.25 mg/kg /day i.m. for 8 weeks.Results:The treatment with MTX to rabbits for 8 weeks resulted in significant changes in serum liver enzymes, as compared to the baseline group. SGOT, SGPT, ALP, and bilirubin were significantly increased (P < 0.001), while total serum protein was significantly decreased. Similarly, 8 weeks of MTX treatment produced significant (P < 0.001) prolongation in PT. PTT was not significantly changed. It was found that serum MDA levels and SOD activity were significantly increased (P < 0.001), while serum GSH levels were significantly decreased (P < 0.001). Adding metformin to MTX is found to be significantly (P < 0.001) reduced the liver function test and shortening of PT and a significant increase in TSP (P < 0.001).Conclusion:It can be concluded that administration of metformin restored the altered liver function parameters and produced significant improvement in liver histopathological findings. Therefore, this additive drug possesses hepatoprotection against MTX-induced hepatotoxicity.

show abstract

“…Products of lipid peroxidation may cause damage to the biological membranes leading to serious cellular injury and leakage of serum marker enzymes like AST, ALT and ALP (Cotran et al, 1994) and finally cell death (Wei, 1998). The prevention of this phenomenon can be considered as hepatoprotective activity (Poon et al, 2003). Estimations of serum transaminases and ALP are the most sensitive tests for diagnosis of liver diseases (Mahendale et al, 1985).…”

Section: Hepatoprotective Activitymentioning

confidence: 99%