Protective effect of an L-type calcium channel blocker, amlodipine, on paracetamol-induced hepatotoxicity in rats

Kaya, Hüseyin; Polat, Beyzagül; Albayrak, Abdulmecit; Mercantepe, Tolga; Bűyűk, Başak

doi:10.1177/0960327118758382

Cited by 9 publications

(6 citation statements)

References 54 publications

(85 reference statements)

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“…Previous studies reported a different mechanism by which amlodipine exhibits beneficial modulation in the context of paracetamol-induced liver inflammation in Wistar rats (PMID: 29441826; PMID: 27829805). 71 , 72 However, the lack of gut microbiota analysis in previous studies hinders comparability with our study. Notably, it has been observed that paracetamol can induce gut dysbiosis in murine models.…”

Section: Discussionmentioning

confidence: 78%

S-amlodipine induces liver inflammation and dysfunction through the alteration of intestinal microbiome in a rat model

Liu,

Fang,

Pan

et al. 2024

Gut Microbes

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S-amlodipine, a commonly prescribed antihypertensive agent, is widely used in clinical settings to treat hypertension. However, the potential adverse effects of long-term S-amlodipine treatment on the liver remain uncertain, given the cautionary recommendations from clinicians regarding its administration in individuals with impaired liver function. To address this, we conducted a study using an eight-week-old male rat model and administered a daily dose of 0.6 ~ 5 mg/kg of S-amlodipine for 7 weeks. Our findings demonstrated that 1.2 ~ 5 mg/kg of S-amlodipine treatment induced liver inflammation and associated dysfunction in rats, further in vitro experiments revealed that the observed liver inflammation and dysfunction were not attributable to direct effects of S-amlodipine on the liver. Metagenome sequencing analysis revealed that S-amlodipine treatment led to alterations in the gut microbiome of rats, with the bloom of E. coli (4.5 ~ 6.6-fold increase) and a decrease in A. muciniphila (1,613.4 ~ 2,000-fold decrease) and B. uniformis (20.6 ~ 202.7-fold decrease), subsequently causing an increase in the gut bacterial lipopolysaccharide (LPS) content (1.4 ~ 1.5-fold increase in feces). S-amlodipine treatment also induced damage to the intestinal barrier and increased intestinal permeability, as confirmed by elevated levels of fecal albumin; furthermore, the flux of gut bacterial LPS into the bloodstream through the portal vein resulted in an increase in serum LPS content (3.3 ~ 4-fold increase). LPS induces liver inflammation and subsequent dysfunction in rats by activating the TLR4 pathway. This study is the first to show that S-amlodipine induces liver inflammation and dysfunction by perturbing the rat gut microbiome. These results indicate the adverse effects of S-amlodipine on the liver and provide a rich understanding of the safety of long-term S-amlodipine administration.

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Section: Discussionmentioning

confidence: 78%

S-amlodipine induces liver inflammation and dysfunction through the alteration of intestinal microbiome in a rat model

Liu,

Fang,

Pan

et al. 2024

Gut Microbes

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“…Other possible markers of liver damage are GSH depletion and oxidative stress (Kaya et al 2018). Fisetin has been shown to have direct antioxidant activity and can also directly increase intracellular levels of GSH (Murtaza et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Fisetin Attenuates Paracetamol-Induced Hepatotoxicity by Regulating CYP2E1 Enzyme

Uğan

Çadırcı

et al. 2023

An. Acad. Bras. Ciênc.

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Paracetamol is one of the drugs that cause hepatic damage. Fisetin has wide pharmacological effects such as anticancer, antiinflammatory and antioxidant. We aimed to evaluate the possible protective effect of fisetin on paracetamol-induced hepatotoxicity. Fisetin was administered at 25 and 50 mg/kg doses. Paracetamol was administered orally at a dose of 2 g/kg for induce hepatotoxicity 1 h after the fisetin and NAC treatments. The rats were sacrificed 24h after the Paracetamol administration.Tumor necrosis factor-alpha (TNF-α), NFκB and CYP2E1 mRNA levels and Superoxide dismutase (SOD) activity, glutathione (GSH) and malondialdehyde (MDA) levels of livers were determined. Serum ALT, AST and ALP levels were measured. Histopathological examinations were also performed. Fisetin administration significantly decreased the ALT, AST and ALP levels in a dose dependent manner. In addition, SOD activity and GSH levels increased, and the MDA level decreased with the treatment of fisetin. The TNF-α, NFκB and CYP2E1 gene expressions were significantly lower in both doses of the fisetin groups compared with the PARA group. Histopathological examinations showed that fisetin has hepatoprotective effects. This study showed that fisetin has the liver protective effects by increasing GSH, decreasing inflammatory mediators and CYP2E1.

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“…In a model of paracetamol‐induced hepatotoxicity in rats, amlodipine reduced the mRNA expression of TNF‐α in the animals' serum. Also, by immunohistochemistry, a reduction was found in TNF‐α expression in the cytoplasm of hepatocytes [45]. Another study showed that nifedipine reduces TNF‐α and IL‐6 levels in the serum of animals in a chilblain model [46].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the anti‐inflammatory effect of 1,4‐dihydropyridine derivatives

Facchin,

Lubschinski,

Moon

et al. 2023

Fundamemntal Clinical Pharma

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IntroductionInflammation is a physiological event that protects the organism against different factors that lead to loss of tissue homeostasis. Dihydropyridine (DHP) derivatives are heterocyclic compounds known for their different biological activities, including anti‐inflammatory activities.ObjectiveTo evaluate the anti‐inflammatory activity of 1,4‐dihydropyridine (1,4‐DHP) derivatives using anti‐inflammatory models in vitro, in RAW264.7 cells induced by lipopolysaccharide (LPS) and in vivo using the acute lung injury (ALI) model in mice.ResultsFifteen compounds derived from 1,4‐DHP were tested in RAW264.7 cells for their cytotoxic effect and cell viability. Thereafter, only the six compounds that showed the highest cell viability were tested for the production or inhibition of the pro‐inflammatory cytokine interleukin 6 (IL‐6). The best compound (compound 4) was tested for its anti‐inflammatory effects in vitro and in vivo, showing inhibition of nitric oxide (NO), pro‐inflammatory cytokines, increased phagocytic activity, and an increase in IL‐10 in vitro. In in vivo tests, compound 4 also reduces the levels of NO, myeloperoxidase (MPO) activity, leukocyte migration, and exudation, as well as reducing the levels of tumor necrosis factor‐alpha (TNF‐α) and IL‐6 and preventing the loss in the lung architecture.ConclusionThis compound showed important anti‐inflammatory activity, with a significant ability to reduce the production of pro‐inflammatory mediators and increase the phagocytic activity of macrophages and anti‐inflammatory mediator secretion (IL‐10). These findings led us to hypothesize that this compound can repolarize the macrophage response to an anti‐inflammatory profile (M2). Moreover, it was also able to maintain its anti‐inflammatory activity in vivo experiments.

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Protective effect of an L-type calcium channel blocker, amlodipine, on paracetamol-induced hepatotoxicity in rats

Cited by 9 publications

References 54 publications

S-amlodipine induces liver inflammation and dysfunction through the alteration of intestinal microbiome in a rat model

S-amlodipine induces liver inflammation and dysfunction through the alteration of intestinal microbiome in a rat model

Fisetin Attenuates Paracetamol-Induced Hepatotoxicity by Regulating CYP2E1 Enzyme

Evaluation of the anti‐inflammatory effect of 1,4‐dihydropyridine derivatives

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