Protection against acetaminophen hepatotoxicity by clofibrate pretreatment: Role of catalase induction

Chen, Chuan; Hennig, Gayle E.; Whiteley, Herbert E.; Manautou, José E.

doi:10.1002/jbt.10043

Cited by 26 publications

(15 citation statements)

References 45 publications

(64 reference statements)

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“…Cyp2c13, Cyp4a10/4a22 and Ste, whereas expression levels of PPARs themselves were not affected. This might be a part of an adaptation response of the hepatocyte against APAP because induction of PPAR has been reported to protect the liver against APAP toxicity in mice (Chen et al, 2002;Manautou et al, 1994;Nicholls-Grzemski et al, 1992. For the metabolizing enzymes, decreased Cyp3a and increased Cyp4a were observed at 24 h. This kind of change is consistent with the previously reported in vivo effects of APAP in rats (Huang et al, 2004).…”

Section: Acetaminophen (Apap)supporting

confidence: 89%

In vitro gene expression analysis of hepatotoxic drugs in rat primary hepatocytes

Suzuki¹,

Inoue²,

Matsushita³

et al. 2008

J of Applied Toxicology

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The study examined the feasibility of screening for hepatotoxicity by an in vitro gene expression analysis using rat primary hepatocytes and Affymetrix Rat Toxicology U34 arrays. Hepatocytes were exposed for 6 or 24 h to eight drugs, with different mechanisms of hepatotoxicity, at one third of the cytotoxic concentration TC 50 , i.e. acetaminophen, cyclophosphamide, clofibrate, chlorpromazine, lithocholic acid, cisplatin, diclofenac and disulfiram. The types of transcriptional changes observed in this study were generally consistent with previously reported in vivo data, although there were some differences. In hierarchical cluster analysis, drugs formed clusters depending on their mode of toxicity against cells. The number of transcripts affected by the cholestatic hepatotoxicants (lithocholic acid and chlorpromazine) or the drugs that rarely cause of hepatotoxicity (cisplatin, diclofenac and disulfiram) were limited compared with the other drugs (acetaminophen, clobifibrate and cyclophosphamide), where they did not induce transcriptional changes apparently related to toxicity. It is concluded that in vitro gene expression analysis of hepatocytes using microarray is a useful tool for evaluating the toxicological profile of drugs and in screening for the direct toxicity of drugs against hepatocytes.

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Section: Acetaminophen (Apap)supporting

confidence: 89%

In vitro gene expression analysis of hepatotoxic drugs in rat primary hepatocytes

Suzuki¹,

Inoue²,

Matsushita³

et al. 2008

J of Applied Toxicology

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“…The increased glutathione availability and catalase activity by clofibrate were not the primary protective pathway in the protection against acetaminophen-induced hepatotoxicity and hepatic lipid peroxidation. [48][49][50] Thus, peroxisome proliferators are likely acting through the L-FABP pathway to scavenge high levels of ROS. Collectively, our data indicate that L-FABP is a strong endogenous antioxidant.…”

Section: Discussionmentioning

confidence: 99%

Antioxidative function of L-FABP in L-FABP stably transfected Chang liver cells

et al. 2005

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C ellular oxidative stress is one of the factors responsible for the propagation of liver diseases, such as hepatitis, cirrhosis, and hepatoma. 1 Several primary antioxidant defense systems such as superoxide dismutase (SOD), catalase, glutathione (GSH), and glutathione peroxidase are present intracellularly. These systems scavenge reactive oxygen species (ROS) such as hydrogen peroxide, superoxide, lipid peroxides, and free radicals. Exposure to oxidative stress may, however, deplete the cellular antioxidant capacity. Therefore, other antioxidant defense systems are expected to play an important role in oxidative stress.Liver fatty acid binding protein (L-FABP) is a 14-kd protein found abundantly in the cytoplasm and the nucleus of hepatocytes. 2,3 L-FABP is very likely to be an effective endogenous antioxidant, because it has high affinity and capacity to bind long-chain fatty acid oxidation products. 4,5 Hepatocyte L-FABP concentration could be as high as 0.4 mmol/L, 6 and it contains a large number of reducing amino acid residues (1 cysteine and 7 methionine residues) in its molecular structure. With an accessible volume enclosed by the molecular surface of L-FABP of 28,600 Å 3,7 the concentration of total methionine residues in L-FABP could be as high as approximately 400 mmol/L. Methionine and cysteine amino acids are regarded as cellular scavengers of activated xenobiotics and

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“…Briefly, C57BL/6 mice were anesthetized with isoflurane and ATZ, 500 mg/kg in saline, or saline alone was given intraperitoneally. This dose of ATZ was previously used in murine models examining efficacy or toxicity of ATZ (31,32). Lungs were harvested 12 and 24 h after ATZ administration.…”

Section: Methodsmentioning

confidence: 99%

S-Glutathionylation of the Rpn2 Regulatory Subunit Inhibits 26 S Proteasomal Function

Żmijewski

Banerjee²,

Abraham

2009

Journal of Biological Chemistry

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Although increased intracellular concentrations of hydrogen peroxide (H 2 O 2 ) are associated with inhibition of 26 S proteasomal activity, the mechanisms responsible for such effects have not been well delineated. In the present studies, we found that direct exposure of purified 26 S proteasomes to H 2 O 2 had negligible effects on their activity, whereas incubation with glutathione and H 2 O 2 produced >80% decrease in chymotrypsin-like and trypsin-like activities. Rpn1 and Rpn2, which are subunits of the 19 S regulatory particle, undergo S-glutathionylation after exposure of purified 26 S proteasomes to glutathione and H 2 O 2 , as well as in HEK 293 cells and neutrophils incubated with H 2 O 2 . Increased oxidation of Rpn1 and Rpn2 cysteine thiols was also found in lung extracts from mice in which catalase was inactivated, a condition associated with augmented intracellular concentrations of H 2 O 2 and diminished 26 S proteasomal activity. Although unoxidized Rpn2 enhanced 20 S proteolytic function in vitro, such potentiation was not found when the 20 S core particle was incubated with oxidized Rpn2. The composition of 26 S proteasomes was not altered after exposure to glutathione and H 2 O 2 , with similar amounts of Rpn1 and Rpn2 in control or oxidized 26 S proteasomal complexes. These findings identify S-glutathionylation of Rpn2 as a contributory mechanism for H 2 O 2 -induced inhibition of 26 S proteasomal function.The ubiquitin-proteasomal system is a major pathway for protein degradation and is involved in multiple cellular processes, including cell cycle control, expression of cell surface receptors, and regulation of intracellular levels of structural and regulatory proteins and transcription factors (1-6). The 26 S proteasome is composed of two main components, a proteolytic 20 S core particle (CP) 2 and an ATPase containing 19 S regulatory particle (RP) (7-10). Ubiquitinated proteins are unfolded in the 19 S RP and then translocated into the 20 S CP where they are degraded. The 20 S CP is composed of four heptameric rings of ␣ and ␤ subunits, with the two inner ␤ rings having proteolytic activity. The 19 S RP consists of a lid and base subcomplex, with the base subcomplex, including the nonenzymatic Rpn1 and Rpn2 toroids, surrounded by six AAA-type ATPases. Rpn1 and Rpn2 appear to play a major regulatory role by modulating the translocation and subsequent degradation of ubiquitinated substrates in the proteolytic core of the 20 S CP (7,(11)(12)(13)(14)(15).Decreased 26 S proteasomal activity, resulting in the accumulation of intracellular proteins, has been associated with aging (16, 17) and with pathophysiologic processes, including heart failure, neurodegenerative diseases, and alcohol induced liver injury (18 -20). A number of recent studies have shown that time-limited inhibition of the 26 S proteasome is beneficial as a therapeutic intervention for malignancies, such as multiple myeloma, and in reducing inflammation and cell injury associated with ischemia-reperfusion injury and transplanta...

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Protection against acetaminophen hepatotoxicity by clofibrate pretreatment: Role of catalase induction

Cited by 26 publications

References 45 publications

In vitro gene expression analysis of hepatotoxic drugs in rat primary hepatocytes

In vitro gene expression analysis of hepatotoxic drugs in rat primary hepatocytes

Antioxidative function of L-FABP in L-FABP stably transfected Chang liver cells

S-Glutathionylation of the Rpn2 Regulatory Subunit Inhibits 26 S Proteasomal Function

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