A new approach on valproic acid induced hepatotoxicity: Involvement of lysosomal membrane leakiness and cellular proteolysis

Pourahmad, Jalal; Eskandari, Mohammad Reza; Kaghazi, Amineh; Shaki, Fatemeh; Shahraki, Javad; Fard, Javad Khalili

doi:10.1016/j.tiv.2012.01.020

Cited by 71 publications

(52 citation statements)

References 42 publications

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“…Some acetyl-CoA enters into the tricarboxylic acid (TCA) cycle for energy generation; some might be converted to ketone bodies, such as acetoacetate, 3-hydroxy butanoic acid and acetone. Several previous reports have shown that VPA and its intramitochondrial metabolites can sequester mitochondrial-free CoA, thereby inhibiting CoA-dependent metabolic processes [42,46,47] . In previous study, the levels of TG, glycerol and FFAs in the plasma and the liver increased in a dose-dependent manner with VPA and increased further in response to the combination of VPA with an HFD, indicating that excessive fats accumulate in vivo after VPA and HFD treatments [40] .…”

Section: Discussionmentioning

confidence: 99%

Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats

et al. 2014

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Aim: To investigate the potential interactive effects of a high-fat diet (HFD) and valproic acid (VPA) on hepatic steatosis and hepatotoxicity in rats. Methods: Male SD rats were orally administered VPA (100 or 500 mg·kg -1 ·d -1 ) combined with HFD or a standard diet for 8 weeks. Blood and liver samples were analyzed to determine lipid levels and hepatic function biomarkers using commercial kit assays. Lowmolecular-weight compounds in serum, urine and bile samples were analyzed using a metabonomic approach based on GC/TOF-MS. Results: HFD alone induced extensive hepatocyte steatosis and edema in rats, while VPA alone did not cause significant liver lesions. VPA significantly aggravated HFD-induced accumulation of liver lipids, and caused additional spotty or piecemeal necrosis, accompanied by moderate infiltration of inflammatory cells in the liver. Metabonomic analysis of serum, urine and bile samples revealed that HFD significantly increased the levels of amino acids, free fatty acids (FFAs) and 3-hydroxy-butanoic acid, whereas VPA markedly decreased the levels of amino acids, FFAs and the intermediate products of the tricarboxylic acid cycle (TCA) compared with the control group. HFD aggravated VPA-induced inhibition on lipid and amino acid metabolism. Conclusion: HFD magnifies VPA-induced impairment of mitochondrial β-oxidation of FFAs and TCA, thereby increases hepatic steatosis and hepatotoxicity. The results suggest the patients receiving VPA treatment should be advised to avoid eating HFD.

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Section: Discussionmentioning

confidence: 99%

Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats

et al. 2014

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“…Although it has been known as a relatively safe drug, at high doses and prolonged use, it can cause life-threatening side effects including gastrointestinal disturbances, liver damage, neurological disturbances, weight gain, pancreatitis, and thrombocytopenia (Dreifuss and Langer 1988;Pourahmad et al 2012). To date, it has been reported in several articles that Fanconi syndrome was associated with VPA therapy (Watanabe et al 2005;Dhillon and Högler 2011).…”

Section: Introductionmentioning

confidence: 99%

Vitamin U has a protective effect on valproic acid-induced renal damage due to its anti-oxidant, anti-inflammatory, and anti-fibrotic properties

et al. 2015

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The aim of present study was to investigate the effect of vitamin U (vit U, S-methylmethionine) on oxidative stress, inflammation, and fibrosis within the context of valproic acid (VPA)-induced renal damage. In this study, female Sprague Dawley rats were randomly divided into four groups: Group I consisted of intact animals, group II was given vit U (50 mg/kg/day, by gavage), group III was given VPA (500 mg/kg/day, intraperitonally), and group IV was given VPA + vit U. The animals were treated by vit U 1 h prior to treatment with VPA every day for 15 days. The following results were obtained in vit U + VPA-treated rats: (i) the protective effect of vit U on renal damage was shown by a significant decrease in histopathological changes and an increase in Na(+)/K(+)-ATPase activity; (ii) anti-oxidant property of vit U was demonstrated by a decrease in malondialdehyde levels and xanthine oxidase activity and an increase in glutathione levels, catalase and superoxide dismutase activities; (iii) anti-inflammatory property of vit U was demonstrated by a decrease in tumor necrosis factor-α, interleukin-1β, monocyte chemoattractant protein-1 levels, and adenosine deaminase activity; (iv) anti-fibrotic effect of vit U was shown by a decrease in transforming growth factor-β, collagen-1 levels, and arginase activity. Collectively, these data show that VPA is a promoter of inflammation, oxidative stress, and fibrosis which resulted in renal damage. Vit U can be proposed as a potential candidate for preventing renal damage which arose during the therapeutic usage of VPA.

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“…Branched chain fatty acids (BCFAs) are generally saturated fatty acids with one or more methyl branches on the carbon chain (Ran-Ressler et al, 2008). In humans, they have been observed in various tissues including skin, brain, blood and cancer cells.…”

Section: Introductionmentioning

confidence: 99%

An in vitro approach to assess the neurotoxicity of valproic acid-induced oxidative stress in cerebellum and cerebral cortex of young rats

Chaudhary

Parvez

2012

Neuroscience

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A new approach on valproic acid induced hepatotoxicity: Involvement of lysosomal membrane leakiness and cellular proteolysis

Cited by 71 publications

References 42 publications

Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats

Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats

Vitamin U has a protective effect on valproic acid-induced renal damage due to its anti-oxidant, anti-inflammatory, and anti-fibrotic properties

An in vitro approach to assess the neurotoxicity of valproic acid-induced oxidative stress in cerebellum and cerebral cortex of young rats

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