Role of lipid peroxidation in acetaminophen-induced hepatotoxicity: comparison with carbon tetrachloride

Kamiyama, T; Sato, Chifumi; Liu, Jian; Tajiri, Kazuo; Miyakawa, Happei; Marumo, Fumiaki

doi:10.1016/0378-4274(93)90073-7

Cited by 33 publications

(19 citation statements)

References 9 publications

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“…Whereas peroxidation of lipids may occur by a Fenton reaction (ferrous plus peroxide), it may also be mediated by peroxynitrite (Rubbo et al, 1994). Lipid peroxidation has been reported to occur in APAP hepatotoxicity (Younes et al, 1986;Hinson et al, 2002); however, this is controversial (Kamiyama et al, 1993). Lipid peroxidation in the APAP-treated WT and KO mice was determined by assaying for 4-HNE covalent binding to liver homogenate.…”

Section: Discussionmentioning

confidence: 99%

Acetaminophen-Induced Hepatotoxicity and Protein Nitration in Neuronal Nitric-Oxide Synthase Knockout Mice

Agarwal¹,

Hennings²,

Rafferty³

et al. 2011

J Pharmacol Exp Ther

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In overdose acetaminophen (APAP) is hepatotoxic. Toxicity occurs by metabolism to N-acetyl-p-benzoquinone imine, which depletes GSH and covalently binds to proteins followed by protein nitration. Nitration can occur via the strong oxidant and nitrating agent peroxynitrite, formed from superoxide and nitric oxide (NO). In hepatocyte suspensions we reported that an inhibitor of neuronal nitric-oxide synthase (nNOS; NOS1), which has been reported to be in mitochondria, inhibited toxicity and protein nitration. We recently showed that manganese superoxide dismutase (MnSOD; SOD2) was nitrated and inactivated in APAP-treated mice. To understand the role of nNOS in APAP toxicity and MnSOD nitration, nNOS knockout (KO) and wild-type (WT) mice were administered APAP (300 mg/kg). In WT mice serum alanine aminotransferase (ALT) significantly increased at 6 and 8 h, and serum aspartate aminotransferase (AST) significantly increased at 4, 6 and 8 h; however, in KO mice neither ALT nor AST significantly increased until 8 h. There were no significant differences in hepatic GSH depletion, APAP protein binding, hydroxynonenal covalent binding, or histopathological assessment of toxicity. The activity of hepatic MnSOD was significantly lower at 1 to 2 h in WT mice and subsequently increased at 8 h. MnSOD activity was not altered at 0 to 6 h in KO mice but was significantly decreased at 8 h. There were significant increases in MnSOD nitration at 1 to 8 h in WT mice and 6 to 8 h in KO mice. Significantly more nitration occurred at 1 to 6 h in WT than in KO mice. MnSOD was the only observed nitrated protein after APAP treatment. These data indicate a role for nNOS with inactivation of MnSOD and ALT release during APAP toxicity.

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Section: Discussionmentioning

confidence: 99%

Acetaminophen-Induced Hepatotoxicity and Protein Nitration in Neuronal Nitric-Oxide Synthase Knockout Mice

Agarwal¹,

Hennings²,

Rafferty³

et al. 2011

J Pharmacol Exp Ther

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“…APAP elicits hepatotoxicity via multifactorial pathways, e.g., APAP-induced hepatic injury has been associated with increased programmed cell death (apoptosis), inflammatory cytokine production, cyclooxygenase (Cox) and reactive oxygen species (ROS) metabolite generation [2], as well as sensitive nuclear transcription factor kappa B (NF-jB) [3], nitric oxide [4], lipid peroxides [5], and reduced glutathione (rGSH) depletion, resulting in ultimate hepatic injury. Other factors, such as active APAP metabolite binding, viz., N-acetyl-p-benzoquinone imine (NAPQI), to target proteins and DNA, have been postulated to be necessary, but not sufficient, for this toxicity [6].…”

Section: Introductionmentioning

confidence: 99%

Green-tea Polyphenols Downregulate Cyclooxygenase and Bcl-2 Activity in Acetaminophen-induced Hepatotoxicity

Chen

2008

Dig Dis Sci

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Acetaminophen (APAP) elicits hepatotoxicity via multifactorial pathways, including increased apoptosis, cyclooxygenase (Cox-2) generation, reactive metabolite release, and glutathione (GSH) depletion. We previously showed that mice that consumed different antioxidants in their diets were protected against APAP-induced hepatotoxicity. We therefore further investigated the mechanisms by which green-tea polyphenols (GrTP) protect against APAP-induced hepatic damage. Mice were administered a diet supplemented with GrTP or vehicle for 5 consecutive days followed by intraperitoneal (IP) injection of a toxic dose of APAP or sham. APAP administration upregulated Cox-2 and B-cell lymphoma-2 (Bcl-2) production and had an effect, albeit minor, on Cox-1 and Fas expression in hepatic tissue. GrTP supplementation normalized APAP induced Cox-2 expression and Bcl-2 activation (P < 0.01), as evidenced by immunohistochemistry and Western blot analyses. Similarly, APAP administration elicited marked depletion (99%) in hepatic reduced GSH (rGSH) and endogenous S-adenosylmethionine (SAMe) concentrations (twofold) when compared with sham. APAP also caused severe centrilobular apoptosis and necrosis accompanied by leukocyte infiltration and marked elevations in the hepatic enzyme, alanine aminotransferase (ALT) released from damaged hepatocytes, and cytokine tumor necrosis factor alpha (TNF-alpha). GrTP improved hepatic histopathology (P < 0.01) and attenuated ALT activity (P < 0.05) and the depletion of rGSH (P < 0.05). In conclusion, GrTP supplementation attenuated hepatotoxicity by normalizing Cox-2 and Bcl-2 activation, suggesting a potential use for GrTP in treatng APAP toxicity.

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“…However, the mechanism of this liver injury is not fully understood. The generation of the reactive oxygen species (ROS) [2] sensitive transcription factor NF-B [3], nitric oxide [4], and lipid peroxides [5] has been postulated to be the major factors involved in this liver injury. Also binding of the metabolically activated APAP (i.e., Nacetyl-p-benoquinone imine (NAPQI) to target proteins and DNA appears to be necessary, but not sufficient for this toxicity [6].…”

Section: Introductionmentioning

confidence: 99%

Diverse antioxidants protect against acetaminophen hepatotoxicity

McClain

Nagasawa

et al. 2005

J. Biochem. Mol. Toxicol.

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The reactive oxygen species-sensitive transcription nuclear factor-kappaB (NF-kappaB) plays a pivotal role in the development of acetaminophen (APAP) hepatotoxicity. We investigated the efficacy of a diverse series of antioxidants in preventing APAP-induced hepatotoxicity. BALB/c mice were divided into four groups and provided with antioxidants incorporated into chow as follows: (1) control diet; or diet supplemented with (2) S-adenosylmethionine (SAMe); (3) green tea polyphenols (GrTP); or (4) (RS)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA). After 5 days on these diets, the animals were further subdivided into (A) given an IP injection with APAP (750 mg/kg), or (B) kept as untreated controls. The animals were sacrificed at 0, 4 h, and 24 h following APAP administration. PAP/vehicle induced marked decreases in hepatic reduced glutathione (GSH) levels and endogenous SAMe concentrations (46%) when compared to controls. APAP also caused severe centrilobular necrosis and marked increase in serum enzyme ALT activity (38-fold). Oral administration of antioxidants significantly attenuated the APAP-induced liver damage and depletion of hepatic GSH. There were profound increases in serum TNF-alpha levels at 4 h following APAP administration in nonsupplemented compared to antioxidant-treated animals, but no significant differences noted after 24 h. Serum amyloid A increased in APAP-challenged mice irrespective of antioxidant treatment. Finally, hepatic SAMe concentrations were drastically decreased 24 h following APAP administration, and these decreases were attenuated by pretreatment with antioxidants. In conclusion, these orally administered antioxidants with dissimilar properties provided protection against liver damage, supporting the potential use of antioxidant therapy in patients with APAP toxicity. This is the first report that GrTP and oral administration of PTCA and SAMe can provide protection against APAP injury in this model.

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Role of lipid peroxidation in acetaminophen-induced hepatotoxicity: comparison with carbon tetrachloride

Cited by 33 publications

References 9 publications

Acetaminophen-Induced Hepatotoxicity and Protein Nitration in Neuronal Nitric-Oxide Synthase Knockout Mice

Acetaminophen-Induced Hepatotoxicity and Protein Nitration in Neuronal Nitric-Oxide Synthase Knockout Mice

Green-tea Polyphenols Downregulate Cyclooxygenase and Bcl-2 Activity in Acetaminophen-induced Hepatotoxicity

Diverse antioxidants protect against acetaminophen hepatotoxicity

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