Protective effect of <i>α</i>‐lipoic acid against chloroquine‐induced hepatotoxicity in rats

Pari, Leelavinothan; Ponnusamy, Murugavel

doi:10.1002/jat.940

Cited by 50 publications

(48 citation statements)

References 42 publications

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“…Previous studies have indicated that plasma GSH as well as vitamin C and vitamin E were decreased in CQ treated rats and α-lipoic acid had a better protective effect than silymarin against CQ-induced hepatotoxicity (Abdel Gayoum et al, 1992;Pari and Murugavel, 2004); and our results are in agreement with these published reports. Preincubation of hepatocytes with vitamin C, quercetin and purpuragalin shows protective effects against CQ-induced toxicity in almost all parameters measured.…”

Section: Discussionsupporting

confidence: 96%

“…A depletion of the antioxidant defense system is involved in the mechanism of cytotoxicity. inhibitor; quercetin a specific CYP2C8 inhibitor; quinidine and cimetidine, which inhibit the 2D6 subfamily; and acetone a non-specific CYP450 inhibitor on the cytotoxicity of CQ were investigated.There are few studies in the literature on the role of antioxidants against CQ-induced hepatotoxicity (Dass and Shah, 2000;Pari and Murugavel, 2004). Previous findings indicated that reduced glutathione (GSH), vitamin C and vitamin E were decreased in CQ-treated rats (Abdel Gayoum et al, 1992).…”

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confidence: 96%

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Cytotoxicity of chloroquine in isolated rat hepatocytes

Jamshidzadeh¹,

Niknahad²,

Kashafi³

2007

J of Applied Toxicology

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Chloroquine is a synthetic quinoline being used as an antimalaria and antirheumatoid agent. Several cases of hepatotoxicity have been reported with the use of chloroquine. However, the mechanism(s) of its hepatotoxic effect is unknown. The purpose of this study was to investigate the cytotoxic mechanism of chloroquine. Cytotoxicity was studied using freshly isolated rat hepatocytes incubated in Krebs-Henseleit buffer under a flow of 95% O(2) and 5% CO(2). Chloroquine was toxic towards hepatocytes and caused cell death with an ED(50) of about 100 mm in 2 h. The events before cell death were rapid GSH depletion and lipid peroxidation. Cytochrome P-450 inhibitors, troleandromycine, cimetidine and quinidine increased the cytotoxicity of chloroquine. Antioxidants significantly prevented the cytotoxicity of chloroquine. Depleting the hepatocyte GSH beforehand increased the chloroquine cytotoxicity. Preventing chloroquine metabolism by specific P-450 inhibitors increased its toxicity, suggesting that a major part of its toxicity is mediated by chloroquine and not by its metabolites. A depletion of the antioxidant defense system is involved in the mechanism of cytotoxicity.

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Section: Discussionsupporting

confidence: 96%

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confidence: 96%

Cytotoxicity of chloroquine in isolated rat hepatocytes

Jamshidzadeh¹,

Niknahad²,

Kashafi³

2007

J of Applied Toxicology

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“…Some investigations indicated the role of reactive metabolites and oxidative stress in chloroquine-induced liver injury. [11][12][13][14] Bioactivation of amodiaquine to a quinone imine metabolite, 15 and oxidative stress have also been suggested to be involved in the development of amodiaquine-induced hepatotoxicity. 16,17 Drug-inflammation interaction is an intriguing model for investigating the mechanisms of drug-induced liver injury.…”

Section: Introductionmentioning

confidence: 99%

Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats

et al. 2016

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“…15,16 LA also has been considered as a candidate therapeutic agent in the treatment or prevention of pathologies associated with an imbalance of oxidoreductive status, such as neurodegeneration, 17 ischemia-reperfusion, 18 and hepatic disorders. 19 There is little data, however, about the effect of LA on fractalkine expression in endotoxemia.In the present study, we examined whether fractalkine is expressed in human umbilical vein endothelial cells (HUVECs) on stimulation with TNF-␣ or IL-1␤ and in arterial endothelial cells in a LPS-induced endotoxemic model in rats. We also evaluated the role of LA in TNF-␣-or IL-1␤-induced expression of fractalkine in HUVECs and endothelial cells in LPS-induced endotoxemia in vivo.…”

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confidence: 99%

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confidence: 99%

Protective Effect of α-Lipoic Acid in Lipopolysaccharide-Induced Endothelial Fractalkine Expression

Sung

Kim

Ahn

et al. 2005

Circulation Research

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Abstract-Fractalkine is a unique chemokine that functions as a chemoattractant as well as an adhesion molecule on endothelial cells activated by proinflammatory cytokines. Alpha-lipoic acid (LA), a naturally occurring dithiol compound, is an essential cofactor for mitochondrial bioenergetic enzymes. LA improves glycemic control, reduces diabetic polyneuropathies, and mitigates toxicity associated with heavy metal poisoning. The effects of LA on processes associated with sepsis, however, are unknown. We evaluated the antiinflammatory effect of LA on fractalkine expression in a lipopolysaccharide-induced endotoxemia model. Tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤) significantly induced fractalkine mRNA and protein expression in endothelial cells. LA strongly suppressed TNF-␣-or IL-1␤-induced fractalkine expression in endothelial cells by suppressing the activities of nuclear factor-B and specificity protein-1. LA also decreased TNF-␣-or IL-1␤-stimulated monocyte adhesion to human umbilical vein endothelial cells. As shown by immunohistochemistry, fractalkine protein expression was markedly increased by treatment with lipopolysaccharide in arterial endothelial cells, endocardium, and endothelium of intestinal villi. LA suppressed lipopolysaccharide-induced fractalkine protein expression and infiltration of endothelin 1-positive cells into the heart and intestine in vivo. LA protected against lipopolysaccharide-induced myocardial dysfunction and improved survival in lipopolysaccharide-induced endotoxemia. These results suggest that LA could be an effective agent to reduce fractalkine-mediated inflammatory processes in endotoxemia. Key Words: ␣-lipoic acid Ⅲ fractalkine Ⅲ endothelial cells Ⅲ inflammation S epsis is a clinical syndrome that represents the systemic response to an infection and is characterized by systemic inflammation and widespread tissue injury. At the site of injury, the endothelium expresses various adhesion molecules that attract leukocytes. 1 At the same time, inflammatory cells are activated and express a variety of adhesion molecules that cause the aggregation and margination of these cells to the vascular endothelium. 2 When the inflammatory response is initiated, a wide variety of chemical mediators are released into circulation. These chemical mediators, including tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤), are associated with the continuation of the inflammatory response. 3 Sepsis is caused mainly by an exaggerated systemic response to endotoxemia induced by gram-negative bacteria and their characteristic cell wall component, lipopolysaccharide (LPS). 4 In mice, challenge with high doses of LPS results in a syndrome resembling septic shock in humans. 5 Fractalkine (CX3CL1) is a structurally novel protein in which a soluble chemokine-like domain is fused to a mucin stalk that extends into the cytoplasm across the cell membrane. 6 Fractalkine is expressed in activated endothelial cells, and its expression is upregulated by TNF-␣, IL-1␤, and LPS. 7,8 As a full-...

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Protective effect of α‐lipoic acid against chloroquine‐induced hepatotoxicity in rats

Cited by 50 publications

References 42 publications

Cytotoxicity of chloroquine in isolated rat hepatocytes

Cytotoxicity of chloroquine in isolated rat hepatocytes

Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats

Protective Effect of α-Lipoic Acid in Lipopolysaccharide-Induced Endothelial Fractalkine Expression

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