Ascorbic acid prevents acetaminophen-induced hepatotoxicity in mice by ameliorating glutathione recovery and autophagy

Kurahashi, Takashi; Lee, Jae Yong; Nabeshima, Atsunori; Homma, Takujiro; Kang, Eun Sil; Saito, Yuka; Yamada, Sohsuke; Nakayama, Toshiyuki; Yamada, Ken Ichi; Miyata, Satoshi; Fujii, Junichi

doi:10.1016/j.abb.2016.06.004

Cited by 33 publications

(15 citation statements)

References 40 publications

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“…Ascorbic acid protected against acetaminophen hepatotoxicity by inhibition of oxidative stress (Kurahashi et al, 2016), and markedly decreased the hepatocyte cell death and liver fibrosis caused by bile acid (Yu et al, 2015).…”

Section: Discussionmentioning

confidence: 93%

Role of Ascorbic Acid Versus Silymarin in Amelioration of Hepatotoxicity Induced by Acrylamide in Adult Male Albino Rats: Histological and Immunohistochemical Study

2020

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Acrylamide (ACR) is a cytotoxic and carcinogenic material. It is a product of a Maillard reaction during the cooking of many types of fried fast food, e.g. potato chip fries, and chicken nuggets. ACR has a severe toxic effect on different body organs. This study investigates the hepatotoxic effect of ACR, and the protective effect of ascorbic acid and silymarin. For this purpose, forty adult, male, albino rats were divided into four groups and received the following treatments for fourteen days: Group I: (the control) normal saline; Group II: ACR only; Group III: ACR and ascorbic acid; and Group IV: ACR and silymarin. Under a light microscope, the liver from rats treated with ACR only presented disturbed liver architecture, degenerated hepatocytes, reduced glycogen contents, congested central vein, and increased collagen fibres with areas of fibrosis. Immunohistochemical examination revealed an increased mean number of CD68-, and α-SMA-positive cells. This indicates the presence of large numbers of stellate macrophages (Kupffer cells) and Hepatic stellate cells (HSCs). The combination of ACR with either ascorbic acid or silymarin resulted in less hepatic degeneration, less fibrosis and fewer CD68 and α-SMA positive cells compared to the ACR only group. In conclusion, treatment with silymarin or ascorbic acid along with ACR appears to alleviate ACR-induced hepatotoxicity with more protection in silymarin treated rats.

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Section: Discussionmentioning

confidence: 93%

Role of Ascorbic Acid Versus Silymarin in Amelioration of Hepatotoxicity Induced by Acrylamide in Adult Male Albino Rats: Histological and Immunohistochemical Study

2020

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“…Accumulating evidence to date has revealed that the induction of autophagy could attenuate sterile inflammatory responses by regulating inflammasome activation, indicating an essential role of autophagy in the amelioration of hepatotoxicity induced by APAP (Kurahashi et al, 2016). Furthermore, sustained autophagy could relieve APAP-induced liver injury by modulating oxidative stress (Han et al, 2010;Yan et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Cardamonin Reduces Acetaminophen-Induced Acute Liver Injury in Mice via Activating Autophagy and NFE2L2 Signaling

Fan

Loor

et al. 2020

Front. Pharmacol.

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Cardamonin (CD), a naturally occurring chalcone derived from the Alpinia species, has been shown to exert antioxidant and anti-inflammatory activity, but its role in the prevention of acetaminophen- (APAP-) induced hepatotoxicity remains elusive. The objective of this study was to determine the protective effects of CD against APAP-induced acute liver injury (ALI) and the underlying mechanisms. Wild-type or transcription factor nuclear factor erythroid 2-related factor 2- (NFE2L2-) deficient mice were treated with CD (50 or 100 mg/kg, i.p.) or vehicle for 24 h. Subsequently, these mice were challenged with APAP (400 mg/kg, i.p.) for 6 h. Liver and blood samples were collected to evaluate liver injury and protein abundance. Treatment with CD significantly reduced APAP-induced hepatotoxicity. Furthermore, CD effectively reduced APAP-induced inflammation by inhibiting high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), and NOD-like receptor protein 3 (NLRP3) signaling. In addition, CD induced activation of sequestosome 1 (p62) and NFE2L2 signaling and facilitated autophagy. By applying autophagy inhibitor 3-methyladenine (3-MA; 20 mg/kg, i.p.), further mechanistic exploration revealed that NFE2L2 deficiency promoted autophagic activity induced by CD treatment, which was conducive to the hepatoprotective effect of CD against APAP-induced hepatoxicity in NFE2L2−/− mice. Overall, data suggest that CD has hepatoprotective effect against APAP-induced ALI, which might contribute to the activation of NFE2L2 and autophagy.

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“…Our recent studies on drug-induced hepatic injuries caused by acetaminophen (APAP) may provide a clue to this issue. (140)(141)(142) APAP is a popular antifebrile and analgesic agent and is generally regarded as a safe medicine. Upon an overdose, however, APAP induces liver injury, which is a leading cause of drug-induced acute liver failure in several countries.…”

Section: Enhanced Detoxification Via Glucuronate Conjugation Reactions May Be Used To Rationalize the Loss Of Asc Synthesismentioning

confidence: 99%

“…While the Akrla -KO mice are more vulnerable to high doses of APAP than the WT mice, Asc supplementation renders the Akrla -KO mouse to be markedly resistant to APAP hepatotoxicity. ( 140 ) These results alone can be simply explained by assuming that Asc exerted a hepatoprotective action via antioxidation against elevated ROS, which are elevated by the CYP reaction and the consumption of glutathione due to glutathione conjugation of NAPQI. Our most recent study, however, had some unexplainable results based on the simple antioxidant action of Asc.…”

Section: Enhanced Detoxification Via Glucuronate Conjugation Reactions May Be Used To Rationalize the Loss Of Asc Synthesismentioning

confidence: 99%

Ascorbate is a multifunctional micronutrient whose synthesis is lacking in primates

Fujii

2021

J. Clin. Biochem. Nutr.

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Ascorbate (vitamin C) is an essential micronutrient in primates, and exhibits multiple physiological functions. In addition to antioxidative action, ascorbate provides reducing power to α-ketoglutarate-dependent non-heme iron dioxygenases, such as prolyl hydroxylases. Demethylation of histones and DNA with the aid of ascorbate results in the reactivation of epigenetically silenced genes. Ascorbate and its oxidized form, dehydroascorbate, have attracted interest in terms of their roles in cancer therapy. The last step in the biosynthesis of ascorbate is catalyzed by L-gulono-γ-lactone oxidase whose gene Gulo is commonly mutated in all animals that do not synthesize ascorbate. One common explanation for this deficiency is based on the increased availability of ascorbate from foods. In fact, pathways for ascorbate synthesis and the detoxification of xenobiotics by glucuronate conjugation share the metabolic processes up to UDP-glucuronate, which prompts another hypothesis, namely, that ascorbate-incompetent animals might have developed stronger detoxification systems in return for their lack of ability to produce ascorbate, which would allow them to cope with their situation. Here, we overview recent advances in ascorbate research and propose that an enhanced glucuronate conjugation reaction may have applied positive selection pressure on ascorbate-incompetent animals, thus allowing them to dominate the animal kingdom.

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Ascorbic acid prevents acetaminophen-induced hepatotoxicity in mice by ameliorating glutathione recovery and autophagy

Cited by 33 publications

References 40 publications

Role of Ascorbic Acid Versus Silymarin in Amelioration of Hepatotoxicity Induced by Acrylamide in Adult Male Albino Rats: Histological and Immunohistochemical Study

Role of Ascorbic Acid Versus Silymarin in Amelioration of Hepatotoxicity Induced by Acrylamide in Adult Male Albino Rats: Histological and Immunohistochemical Study

Cardamonin Reduces Acetaminophen-Induced Acute Liver Injury in Mice via Activating Autophagy and NFE2L2 Signaling

Ascorbate is a multifunctional micronutrient whose synthesis is lacking in primates

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