Early loss of large genomic DNA in vivo with accumulation of Ca2+ in the nucleus during acetaminophen-induced liver injury

Ray, Sidhartha D.; Sorge, Christopher L.; Raucy, Judy L.; Corcoran, George B.

doi:10.1016/0041-008x(90)90254-r

Cited by 111 publications

(69 citation statements)

References 19 publications

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“…We next analyzed whether the amount of TUNEL-positive cells correlated with the extent of DNA fragmentation as estimated by a biochemical method. Therefore, we determined the percentage of DNA released from the hepatocyte nuclei into cytoplasms during necrosis as described by Ray et al 6 In accordance with TUNEL, we found a clear and significant (P Ͻ .001) difference in the extent of DNA fragmentation 10 hours after APAP application between WT mice (10.6 Ϯ 4.1%) and Dnase1 KO mice (1.4 Ϯ 0.9%) (Fig. 5A).…”

Section: Quantification Of Apap-induced Liver Necrosis Inmentioning

confidence: 50%

“…APAP-induced necrosis was evaluated via HE staining and correlated to DNA damage as visualized via TUNEL, because it was previously shown to be a prominent parameter of APAP toxicity. 4,6,20 For this, serial liver sections of each time point were treated with either HE staining or TUNEL.…”

Section: Quantification Of Apap-induced Liver Necrosis Inmentioning

confidence: 99%

“…2,3 Nuclear accumulation of Ca 2ϩ and DNA damage have been described to occur during APAPinduced cytotoxicity of murine hepatocytes in vitro and in vivo. [4][5][6] DNA damage seems to be an important event, because APAP toxicity was prevented by known inhibitors of Ca 2ϩ -dependent endonucleases, including Ca 2ϩ -chelators such as aurintricarboxylic acid, glycol ether diamine tetra-acetic acid, and the Ca 2ϩ -calmodulin antagonist chlorpromazine. 5,7,8 However, the nucleases involved in APAP-induced DNA damage have not yet been identified.…”

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Deoxyribonuclease 1 aggravates acetaminophen-induced liver necrosis in male CD-1 mice

et al. 2006

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An overdose of acetaminophen (APAP) (N-acetyl-p-aminophenol) leads to hepatocellular necrosis induced by its metabolite N-acetyl-p-benzoquinone-imine, which is generated during the metabolic phase of liver intoxication. It has been reported that DNA damage occurs during the toxic phase; however, the nucleases responsible for this effect are unknown. In this study, we analyzed the participation of the hepatic endonuclease deoxyribonuclease 1 (DNASE1) during APAP-induced hepatotoxicity by employing a Dnase1 knockout (KO) mouse model. Male CD-1 Dnase1 wild-type (WT) (Dnase1 ؉/؉ ) and KO (Dnase1 ؊/؊ ) mice were treated with 2 different doses of APAP. Hepatic histopathology was performed, and biochemical parameters for APAP metabolism and necrosis were investigated, including depletion of glutathione/glutathione-disulfide (GSH؉GSSG), ␤-nicotinamide adenine dinucleotide (NADH؉NAD ؉ ), and adenosine triphosphate (ATP); release of aminotransferases and Dnase1; and occurrence of DNA fragmentation. As expected, an APAP overdose in WT mice led to massive hepatocellular necrosis characterized by the release of aminotransferases and depletion of hepatocellular GSH؉GSSG, NADH؉NAD ؉ , and ATP. These metabolic events were accompanied by extensive DNA degradation. In contrast, Dnase1 KO mice were considerably less affected. In conclusion, whereas the innermost pericentral hepatocytes of both mouse strains underwent necrosis to the same extent independent of DNA damage, the progression of necrosis to more outwardly located cells was dependent on DNA damage and only occurred in WT mice. Dnase1 aggravates APAP-induced liver necrosis. A cetaminophen, a widely used analgesic, is one of the most commonly overdosed pharmaceuticals. 1 Overdose leads to liver necrosis caused by the electrophilic metabolite N-acetyl-p-benzoquinoneimine (NAPQI), which is generated via oxidation of acetaminophen (APAP) by a microsomal cytochrome P450 containing mixed-function oxidase system. 2 Subsequent detoxication of NAPQI by cellular glutathione leads to depletion of glutathione/glutathione-disulfide (GSHϩGSSG) followed by NAPQI accumulation and induction of necrosis due to protein arylation and severe oxidative stress. 2,3 Nuclear accumulation of Ca 2ϩ and DNA damage have been described to occur during APAPinduced cytotoxicity of murine hepatocytes in vitro and in vivo. 4-6 DNA damage seems to be an important event, because APAP toxicity was prevented by known inhibitors of Ca 2ϩ -dependent endonucleases, including Ca 2ϩ -chelators such as aurintricarboxylic acid, glycol ether diamine tetra-acetic acid, and the Ca 2ϩ -calmodulin antagonist chlorpromazine. 5,7,8 However, the nucleases involved in APAP-induced DNA damage have not yet been identified.Deoxyribonuclease 1 (DNASE1), a Ca 2ϩ /Mg 2ϩ -dependent secreted endonuclease with a pH optimum of approximately 7.5, hydrolyzes double-stranded DNA generating 5Ј-phospho-tri-and/or tetra-oligonucleotides. 9,10 DNASE1 gene expression has been demonstrated in a number of different organs of the urogenital and ...

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Section: Quantification Of Apap-induced Liver Necrosis Inmentioning

confidence: 50%

Section: Quantification Of Apap-induced Liver Necrosis Inmentioning

confidence: 99%

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confidence: 99%

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Deoxyribonuclease 1 aggravates acetaminophen-induced liver necrosis in male CD-1 mice

et al. 2006

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“…Indeed, it is likely that the extent, timing, and duration of GSH depletion could account for conflicting results in the literature. 38 Although nuclear apoptosis-like changes have been observed in vivo in the liver of APAP-treated mice, [6][7][8]19 the above-cited inhibition of caspase activity 36 and the lack of difference in extent of liver injury in TNF-␣ knockout mice suggest that apoptosis may not be an important factor. 39 However, both of these studies employed a single, large dose of APAP.…”

Section: Discussionmentioning

confidence: 99%

“…Among drug toxicities, acetaminophen (APAP) toxicity has been extensively studied for decades, although controversy still continues regarding the precise mechanism of toxicity. Recent evidence has suggested apoptosis as contributing to APAP toxicity, although this is mainly based on TUNEL staining or DNA fragmentation, [6][7][8] which may not reliably distinguish apoptosis and necrosis. 9,10 This raises 2 major possibilities, which are considered in this report: (1) APAP might induce apoptosis by causing intracellular stress, and/or (2) APAP might increase the susceptibility to apoptosis induced by the extrinsic pathway.…”

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Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-α-induced apoptosis in cultured mouse hepatocytes

et al. 2002

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The effect of reduced glutathione (GSH) depletion by acetaminophen (APAP), diethylmaleate (DEM), or phorone on the mode of cell death and susceptibility to tumor necrosis factor (TNF)-induced cell death was studied in cultured mouse hepatocytes. Dose-dependent necrosis was the exclusive mode of cell death with APAP alone, but the addition of TNF-␣ induced a switch to about half apoptosis without changing total loss of viability. This effect was seen at 1

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Cell Death and Apoptosis

Ray¹,

Corcoran²

2009

General, Applied and Systems Toxicology

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Toxicants cause cell death via apoptosis, necrosis and apocrosis. The last decade of the twentieth century and the first decade of the new millennium witnessed over one million reports exploring the occurrence of apoptosis, its mechanisms, and therapeutic implications. Cooperative efforts of every compartment of the cell, as well as various micro and macromolecules, orchestrate this form of cell death. Apoptosis has captured the attention of scientists because retrospective analyses of the mechanisms of human disease show that apoptotic factors either contribute to disease development or, in large measure, account for it. Although apoptosis has been viewed as diametrically opposed to necrotic cell death, they share a number of key features in common. Apoptosis can be viewed as versatile and even malleable, whereas other forms of cell death are not; apoptosis signaling pathways are sharply defined but others are not. This chapter discusses the overall mechanistic frameworks that come under the influence of drugs, chemicals, and stressors, the initiation and progression of apoptosis during organ toxicity, and an up‐to‐date account of the morphological, biochemical, genetic and molecular events that characterize apoptosis. Emphasis has been placed upon insights from both in vivo and in vitro models. This chapter is intended to serve a resource that presents the current fundamentals of apoptosis and its scientific bases in this significant and rapidly evolving field.

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Early loss of large genomic DNA in vivo with accumulation of Ca2+ in the nucleus during acetaminophen-induced liver injury

Cited by 111 publications

References 19 publications

Deoxyribonuclease 1 aggravates acetaminophen-induced liver necrosis in male CD-1 mice

Deoxyribonuclease 1 aggravates acetaminophen-induced liver necrosis in male CD-1 mice

Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-α-induced apoptosis in cultured mouse hepatocytes

Cell Death and Apoptosis

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