Purification, antibody production, and partial amino acid sequence of the 58-kDa acetaminophen-binding liver proteins

Bartolone, John B.; Birge, Raymond B.; Bulera, Steven J.; Bruno, Mary K.; Nishanian, Ervant; Cohen, Steven D.; Khairallah, Edward A.

doi:10.1016/0041-008x(92)90004-c

Cited by 81 publications

(40 citation statements)

References 40 publications

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“…Second, the rate of GSH consumption, indicative of the quantitative formation of the thiol-reactive NAPQI, were similar in both genotypes. Finally, and importantly, the extent of the covalent adduct formation to the major APAP-binding protein, the 58-kD ABP, 41,42 was not changed in the double-knockout mice. Again, this indicates that the primary early events of drug bioactivation, selective target protein binding, and the ensuing signaling that triggers centrilobular hepatocyte injury are unlikely to be mediated by TNF or LT-␣.…”

Section: Discussionmentioning

confidence: 95%

“…32,41 The most prominent target was the 58-kd ABP (acetaminophenbinding protein), which has been suggested to be a preferred target for APAP binding in cytosol 41 and shows sequence similarity to a selenium-binding protein. 42,43 Two other targets were also quite prominent, an unidentified protein of ϳ56 kd and a 44-kD target, which has been shown to originate from the endoplasmic reticulum 44 identified as a subunit of glutamine synthetase. 45 Quantitative image analysis of binding to the 58-kD ABP and the 44-kD ABP revealed no significant difference between the wild-type and knockout mice at 4 hours (data not shown).…”

Section: Cyp2e1 and Cyp1a2 Activities In Tnf/lt-␣-deficient Micementioning

confidence: 99%

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Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-α gene knockout mice

et al. 1998

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Recent evidence suggests that macrophages and/or other nonparenchymal cells may release important mediators contributing to the hepatic necrosis induced by high doses of acetaminophen (APAP). The nature and causative role of these mediators has remained elusive, however. To investigate the role of the proinflammatory cytokine, tumor necrosis factor (TNF) in the initiation and early propagation of APAP-induced liver injury, we have used mice deficient in both TNF and the closely related lymphotoxin-␣ (LT-␣). Male TNF/LT-␣ knockout mice and C57BL/6 wild-type mice were treated with a hepatotoxic dose of APAP (400 mg/kg, intraperitoneally), and the development of liver injury was monitored over 8 hours. Both genotypes exhibited similar basal activities of hepatic cytochrome P450 2E1 and 1A2. After APAP administration, both the rate of glutathione consumption and the extent of subsequent selective protein binding did not differ significantly in the knockout and wild-type mice. The TNF/LT-␣-deficient mice developed severe centrilobular necrosis and exhibited highly increased levels of serum alanine aminotransferase and aspartate aminotransferase, the extent of which was not significantly different from that in wild-type mice. In C57BL/6 mice exposed to APAP, no increases in hepatic transcripts of TNF or LT-␣ were found by reverse transcription-polymerase chain reaction, nor was immunoreactive serum TNF detected by enzyme-linked immunosorbent assay over 8 hours posttreatment. These data indicate that, in the absence of the genes encoding for TNF and LT-␣, APAP bioactivation was not altered and mice still developed severe hepatic necrosis. Thus, TNF is unlikely to be a key mediator in the early pathogenesis of APAP-induced hepatotoxicity. (HEPATOLOGY 1998;27:1021-1029.)

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Section: Discussionmentioning

confidence: 95%

Section: Cyp2e1 and Cyp1a2 Activities In Tnf/lt-␣-deficient Micementioning

confidence: 99%

Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-α gene knockout mice

et al. 1998

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“…Among them a few have been previously identified, including three isomers of selenium-binding proteins in spots 9, 10, and 14 and mitochondrial aldehyde dehydrogenase in spot 15 (17,18,22). However, five additional proteins, which were identified previously by other methods, have not been found among our set, including glutamine synthetase subunit (19), glutamate dehydrogenase (19), N-10-formyltetrahydrofolate dehydrogenase (20), lamin-A (23), and carbamyl phosphate synthetase I (24).…”

Section: Discussionmentioning

confidence: 99%

Identification of the Hepatic Protein Targets of Reactive Metabolites of Acetaminophen in Vivoin Mice Using Two-dimensional Gel Electrophoresis and Mass Spectrometry

Qiu¹,

Benet²,

Burlingame³

1998

Journal of Biological Chemistry

298

232

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Liver toxicity following an overdose of acetaminophen is frequently considered a model for drug-induced hepatotoxicity. Extensive studies over many years have established that such toxicity is well correlated with liver protein arylation by acetaminophen metabolites. Identification of protein targets for covalent modifications is a challenging but necessary step in understanding how covalent binding could lead to liver toxicity. Previous approaches suffered from technical limitations, and thus over the last 10 years heroic efforts were required to determine the identity of only a few target proteins. We present a new mass spectrometry-based strategy for identification of all target proteins that now provides a comprehensive survey of the suite of liver proteins modified. After administration of radiolabeled acetaminophen to mice, the proteins in the liver tissue lysate were separated by two-dimensional polyacrylamide gel electrophoresis. In-gel digestion of the radiolabeled gel spots gave a set of tryptic peptides, which were analyzed by matrix-assisted laser desorption ionization mass spectrometry. Interrogation of data bases based on experimentally determined molecular weights of peptides and product ion tags from postsource decay mass spectra was employed for the determination of the identities of modified liver proteins. Using this method, more than 20 new drug-labeled proteins have been identified.

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“…In livers of untreated WT and IL-1ra KO mice, APAP adducts were barely detected, but the intraperitoneal injection of APAP (100-300 mg/kg) increased the amount of APAP adducts in a dose-dependent manner to a larger extent in WT mice than in IL-1ra KO ones (Figure 1c). 23,24 We next examined blood APAP concentration and intrahepatic GSH levels in both strain mice at 1 and 2 h after APAP challenge (200 mg/kg), because the half-life of APAP was 1-3 h in vivo. 25 At the indicated time intervals, blood APAP levels was significantly higher in IL-1ra KO mice than in WT mice (Figure 1d).…”

Section: Reduced Susceptibility Of Il-1ra-deficient Hepatocytes To Apmentioning

confidence: 99%

Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist

Ishibe

Kimura

Ishida

et al. 2009

Laboratory Investigation

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Acetaminophen (APAP) induced increases in intrahepatic expression of interleukin (IL)-1a, IL-1b, and IL-1 receptor antagonist (IL-1ra), when administered intraperitoneally. These observations prompted us to define the pathophysiological roles of IL-1ra in APAP-induced liver injury. Compared with wild-type (WT) mouse-derived hepatocytes, IL-1ra-deficient (IL-1ra KO)-derived hepatocytes exhibited more resistance against APAP but not APAP-derived major toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Moreover, the amounts of a major APAP adduct (selenium-binding protein), an indicator of NAPQI generation from APAP, was significantly lower in IL-1ra KO mice than WT mice with depressed intrahepatic expression of CYP1A2, CYP2E1, and CYP3A11, the enzymes crucially involved in NAPQI generation from APAP. These observations would indicate that IL-1ra deficiency impaired APAP metabolism. IL-1a and IL-1b were expressed to similar extents in livers of untreated IL-1ra KO and WT mice. By contrast, the intranuclear amount of p65 of NF-kB, which can suppress the gene expression of CYP1A2, CYP2E1, and CYP3A11, was higher in untreated IL-1ra KO than WT mice. Moreover, when mice were intraperitoneally administered APAP (200 mg/kg), IL-1ra KO mice exhibited attenuated APAP-induced liver injury as evidenced by reductions in serum alanine transferase levels and histopathological changes such as centrilobular necrosis, hemorrhages, and leukocyte infiltration. Finally, when given 12 h before APAP challenge, IL-1a repressed the intrahepatic expression of CYP1A2, CYP2E1, and CYP3A11, eventually reducing APAP-induced liver injury, along with reduction in APAP adducts. Collectively, NF-kB was activated without any stimuli by the genetic disruption of IL-1ra, and suppressed cytochrome P450 enzyme expression, thereby reducing APAP-induced liver injury.

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Purification, antibody production, and partial amino acid sequence of the 58-kDa acetaminophen-binding liver proteins

Cited by 81 publications

References 40 publications

Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-α gene knockout mice

Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-α gene knockout mice

Identification of the Hepatic Protein Targets of Reactive Metabolites of Acetaminophen in Vivoin Mice Using Two-dimensional Gel Electrophoresis and Mass Spectrometry

Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist

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