Clofibrate Pretreatment Diminishes Acetaminophen′s Selective Covalent Binding and Hepatotoxicity

Manautou, José E.; Hoivik, Debie J.; Tveit, Ann; Hart, Susan; Khairallah, Edward A.; Cohen, Steven D.

doi:10.1006/taap.1994.1250

Cited by 70 publications

(104 citation statements)

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“…There is mounting evidence that PPARβ/δ plays a role in ameliorating the hepatotoxic effects of a wide range of xenobiotics including arsenic and acetaminophen (APAP). Interestingly, a similar hepatoprotective role has been noted for PPARα [37][38][39] and PPARγ [40] agonists, although the mechanism of this response is not clear. Studies performed with hepatocytes from wild type and PPARβ/δ −/− mice clearly demonstrate that PPARβ/δ plays a pivotal role in ameliorating oxidative stress induced by the hepatoxicant arsenic (Fig.…”

Section: Discussionmentioning

confidence: 61%

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Coleman

Prabhu

Thompson

et al. 2007

Free Radical Biology and Medicine

104

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Liver insufficiency and damage is a major cause of death and disease worldwide and may result from exposure to environmental toxicants, specific combinations or dosages of pharmaceuticals and microbial metabolites. The generation of reactive intermediates, in particular 4-hydroxynonenal (4-HNE), is a common event in liver damage caused by a variety of hepatotoxic drugs and solvents. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in the transcriptional regulation of lipid metabolism as well as other biological functions. Importantly, we have observed that the PPARβ/δ −/− mouse is more susceptible to chemically-induced hepatotoxicity than its wildtype counterpart, and our objective in this study was to elucidate the mechanism(s) by which PPARβ/δ confers protection to hepatocytes. We hypothesized that PPARβ/ δ plays a protective role by responding to toxic lipids and altering gene expression accordingly. In support, oxidized-VLDL and constituents including 13-S-hydroxyoctadeca-dienoic acid (13(S)-HODE) and 4-HNE are PPARβ/δ ligands. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPARβ/δ subtype while 4-hyroxy-hexenal (4-HHE), 4-oxo-2-Nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal did not activate this receptor. Increasing PPARβ/δ activity with a synthetic agonist decreased sensitivity of hepatocytes to 4-HNE and other toxic agents, whereas inhibition of this receptor had the opposite result. Gene expression microarray analysis identified several important PPARβ/δ-regulated detoxification enzymes involved in 4-HNE metabolism that are regulated at the transcript level. This research established 4-HNE as an endogenous modulator of PPARβ/δ activity and raises the possibility that agonists of this nuclear receptor may be utilized to prevent or treat liver disease associated with oxidative damage.

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Section: Discussionmentioning

confidence: 61%

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Coleman

Prabhu

Thompson

et al. 2007

Free Radical Biology and Medicine

104

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“…In their pioneering work, Mehendale and colleagues first demonstrated autoprotection in rats in the early 1990s using the hepatotoxicant carbon tetrachloride (CCl 4 ) 18 . Similarly, studies conducted by our group have demonstrated both autoprotection/heteroprotection in mice and that pretreatment of mice with various xenobiotics with different modes of action results in considerable reduction in the severity of APAP toxicity 11, 17 . Administration of subtoxic doses of clofibrate (CFB), an activator of the peroxisome proliferator-activated receptor alpha (PPARα), protects mice from APAP hepatotoxicity (APAP heteroprotection) 17 .…”

Section: Autoprotection and Heteroprotectionmentioning

confidence: 61%

“…Similarly, studies conducted by our group have demonstrated both autoprotection/heteroprotection in mice and that pretreatment of mice with various xenobiotics with different modes of action results in considerable reduction in the severity of APAP toxicity 11, 17 . Administration of subtoxic doses of clofibrate (CFB), an activator of the peroxisome proliferator-activated receptor alpha (PPARα), protects mice from APAP hepatotoxicity (APAP heteroprotection) 17 . Similarly, the APAP heteroprotection phenomenon has also been demonstrated with hepatotoxicants such as thioacetamide 19 , CCl 4 20, 21 , chloroform, and bromobenzene 20 .…”

Section: Autoprotection and Heteroprotectionmentioning

confidence: 61%

“…Similarly, the APAP heteroprotection phenomenon has also been demonstrated with hepatotoxicants such as thioacetamide 19 , CCl 4 20, 21 , chloroform, and bromobenzene 20 . Results from initial studies using repeated doses of CFB show that protection against APAP toxicity is associated with the prevention of GSH depletion and less covalent binding of the reactive intermediate of APAP with the cellular proteins 17 . A subsequent study showed that a single dose of CFB prior to intoxication with APAP also protects against APAP hepatotoxicity, but neither produces changes in reactive intermediate covalent binding nor GSH depletion 22 .…”

Section: Autoprotection and Heteroprotectionmentioning

confidence: 99%

“…The advent of high-throughput gene microarray and proteomic analysis has facilitated the identification of global changes in gene and protein expression. Using these modern tools, novel mechanisms implicated in adaptation to APAP toxicity have been identified in the rodent models of autoprotection/heteroprotection 11– 17 . An update on the experimental models of hepatoprotection (both autoprotection and heteroprotection) (summarized in Figure 1) and their potential diagnostic/therapeutic usefulness in the prognosis and treatment of APAP-induced hepatotoxicity will be summarized in the current review.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

From hepatoprotection models to new therapeutic modalities for treating liver diseases: a personal perspective

Rudraiah

Manautou

2016

F1000Res

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A variety of rodent models of hepatoprotection have been developed in which tolerance to acetaminophen-induced hepatotoxicity occurs. Autoprotection/heteroprotection is a phenomenon where prior exposure to a mildly toxic dose of toxicant confers protection against a subsequently administered higher dose of the same toxicant (as in the case of autoprotection) or to a different toxicant (referred to as heteroprotection). Multiple mechanisms regulate this adaptive response, including hepatocellular proliferation, proteostasis, enhanced expression of cytoprotective genes, and altered tissue immune response. In this review, we will discuss recent findings that highlight the complexity of these adaptive mechanisms and we also outline the usefulness of these findings to devise therapeutic and/or diagnostic tools for acetaminophen-induced liver damage in patients.

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Clofibrate pretreatment in mice confers resistance against hepatic lipid peroxidation

Nicholls-Grzemski

Belling

Priestly³

et al. 2000

J. Biochem. Mol. Toxicol.

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Clofibrate Pretreatment Diminishes Acetaminophen′s Selective Covalent Binding and Hepatotoxicity

Cited by 70 publications

References 0 publications

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

From hepatoprotection models to new therapeutic modalities for treating liver diseases: a personal perspective

Clofibrate pretreatment in mice confers resistance against hepatic lipid peroxidation

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