Knockdown of superoxide dismutase 2 enhances acetaminophen-induced hepatotoxicity in rat

Yoshikawa, Yukitaka; Morita, Mayu; Hosomi, Hiroko; Tsuneyama, Koichi; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1016/j.tox.2009.07.017

Cited by 24 publications

(16 citation statements)

References 23 publications

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“…We found that in hepatocytes the nNOS inhibitor 7-nitroindazole inhibited APAP-induced nitration and toxicity (Burke et al, 2010). The finding that in APAP hepatotoxicity MnSOD is nitrated with loss of activity coupled with the finding that MnSOD heterozygote mice (Fujimoto et al, 2009) and MnSOD knockdown rats (Yoshikawa et al, 2009) are much more sensitive to APAP hepatotoxicity than the wild type further supports a role for peroxynitrite in the toxicity. MnSOD limits peroxynitrite formation, and with loss of activity upon nitration, additional peroxynitrite would be formed.…”

Section: Discussionsupporting

confidence: 55%

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: Discussionsupporting

confidence: 55%

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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“…However, total liver protein binding is similar between mice and rats (McGill et al, 2012b) and other indicators of cell dysfunction, such as impaired energy metabolism and oxidative stress, have been reported by some in the latter species (Katayre and Satav, 1989; Yoshikawa et al, 2009). To determine whether or not ASS can detect injury or stress in a rat model of APAP overdose, rats were injected with 1 or 2 g/kg APAP and sacrificed at various times.…”

Section: Resultsmentioning

confidence: 87%

Argininosuccinate synthetase as a plasma biomarker of liver injury after acetaminophen overdose in rodents and humans

et al. 2014

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Context New biomarkers are needed in acetaminophen (APAP) hepatotoxicity. Plasma argininosuccinate synthetase (ASS) is a promising candidate. Objective Characterize ASS in APAP hepatotoxicity. Methods ASS was measured in plasma from rodents and humans with APAP hepatotoxicity. Results In mice, ASS increased before injury, peaked before ALT, and decreased rapidly. Fischer rats had a greater increase in ASS relative to ALT. Patients with abnormal liver test results had very high ASS compared to controls. ASS appeared to increase early in some patients, and declined rapidly in all. Conclusions : ASS may be a useful biomarker of acute cell death in APAP hepatotoxicity.

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“…In further studies, we determined if reduced sensitivity of Cav-1 −/− mice to acetaminophen was associated with alterations in levels of GSH and antioxidants important in protecting against liver injury (Nakae et al , 1990; Ferret et al , 2001; Chiu et al , 2003a; Fujimoto et al , 2009; Mladenovic et al , 2009; Yoshikawa et al , 2009). GSH was detected in livers of wild type and Cav-1 −/− mice; however levels of this antioxidant were significantly lower in Cav-1 −/− mice (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity

Gardner

Gray

Joseph

et al. 2010

Toxicology and Applied Pharmacology

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Caveolin-1 (Cav-1) is a membrane scaffolding protein which functions to regulate intracellular compartmentalization of various signaling molecules. In the present studies, transgenic mice with a targeted disruption of the Cav-1 gene (Cav-1 −/− ) were used to assess the role of Cav-1 in acetaminophen-induced hepatotoxicity. Treatment of wild type mice with acetaminophen (300 mg/ kg) resulted in centrilobular hepatic necrosis and increases in serum transaminases. This was correlated with decreased expression of Cav-1 in the liver. Acetaminophen-induced hepatotoxicity was significantly attenuated in Cav-1 −/− mice, an effect that was independent of acetaminophen metabolism. Acetaminophen administration resulted in increased hepatic expression of the oxidative stress marker, lipocalin 24p3, as well as hemeoxygenase-1, but decreased glutathione and superoxide dismutase-1; no differences were noted between the genotypes suggesting that reduced toxicity in Cav-1 −/− mice is not due to alterations in anti-oxidant defense. In wild type mice, acetaminophen increased mRNA expression of the pro-inflammatory cytokines, interleukin-1β and monocyte chemoattractant protein-1 (MCP-1), as well as cyclooxygenase-2, while 15-lipoxygenase (15-LOX), which generates anti-inflammatory lipoxins, decreased. Acetaminophen-induced changes in MCP-1 and 15-LOX expression were greater in Cav-1 −/− mice. Although expression of tumor necrosis factor-α, a potent hepatocyte mitogen, was up-regulated in the liver of Cav-1 −/− mice after acetaminophen, expression of proliferating cell nuclear antigen and survivin, markers of cellular proliferation, were delayed which may reflect the reduced need for tissue repair. Taken together, these data demonstrate that Cav-1 plays a role in promoting inflammation and toxicity during the pathogenesis of acetaminophen-induced injury.

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Knockdown of superoxide dismutase 2 enhances acetaminophen-induced hepatotoxicity in rat

Cited by 24 publications

References 23 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

Argininosuccinate synthetase as a plasma biomarker of liver injury after acetaminophen overdose in rodents and humans

Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity

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