Peroxisome proliferators protect against paracetamol hepatotoxicity in mice

Nicholls-Grzemski, Felicity A.; Calder, I. C.; Priestly, Brian G.

doi:10.1016/0006-2952(92)90193-m

Cited by 33 publications

(20 citation statements)

References 6 publications

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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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“…for 10 days. This treatment regimen not only results in peroxisome proliferation but also confers protection against hepatotoxicants such as acetaminophen (Nicholls-Grzemski et al, 1992;Manautou et al, 1994). Livers were removed, snap frozen in liquid nitrogen, and stored at Ϫ80°C until assayed.…”

Section: Methodsmentioning

confidence: 99%

Induction of Hepatic Transporters Multidrug Resistance-Associated Proteins (Mrp) 3 and 4 by Clofibrate Is Regulated by Peroxisome Proliferator-Activated Receptor α

Moffit¹,

Aleksunes²,

Maher³

et al. 2006

J Pharmacol Exp Ther

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Hepatic transporters play a vital role in the disposition of endogenous compounds and xenobiotics in the liver. The current study investigates the expression and regulation of hepatic efflux transporters in response to treatment with the peroxisome proliferator-activated receptor (PPAR)␣ agonist clofibrate (CFB). Changes in mRNA and protein levels for several hepatic transporters were assessed in male CD-1 mice after 10 days of CFB dosing (500 mg/kg i.p.). Administration of CFB up-regulated mRNA levels for breast cancer resistance protein (Bcrp) and multidrug resistance-associated proteins 3 and 4 (Mrp3 and Mrp4, respectively). Western blot analysis confirmed that CFB enhances protein expression of liver Bcrp, Mrp3, and Mrp4 in CD-1 mice. To further characterize the regulation of these hepatic transporters, CFB-mediated changes in transporter mRNA levels were assessed in wild-type (sv/129) and PPAR␣-null male mice. Wild-type mice treated with CFB showed similar changes in mRNA levels for all of these transporters, whereas the PPAR␣-null mice did not. Although protein expression of Mrp3 and Mrp4 in the wild-type mice correlated well with changes in mRNA levels, Bcrp protein was not upregulated by CFB treatment. These results show that PPAR␣ activation by CFB coordinately regulates the hepatic efflux transporters Mrp3 and Mrp4. Induction of Mrp3 and Mrp4 by CFB may alter the disposition of toxicants and xenobiotics that are substrates for these transporters.

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“…Clofibrate (CFB) has been used extensively to investigate the mechanistic basis of this protection. Pretreatment of mice for 10 days with CFB completely prevents acetaminophen (APAP)-induced hepatotoxicity (Nicholls-Grzemski et al, 1992;Manautou et al, 1994). APAP toxicity is highly dependent upon bioactivation by cytochrome P450 enzymes to the reactive intermediate N-acetyl-p-benzoquinoneimine (NAPQI), depletion of hepatocellular glutathione (GSH), adduct formation to target hepatic proteins and generation of oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Role of NAD(P)H:quinone oxidoreductase 1 in clofibrate-mediated hepatoprotection from acetaminophen

et al. 2007

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Mice pretreated with the peroxisome proliferator clofibrate (CFB) are resistant to acetaminophen (APAP) hepatotoxicity. Whereas the mechanism of protection is not entirely known, CFB decreases protein adducts formed by the reactive metabolite of APAP, N-acetyl-p-benzoquinone imine (NAPQI). NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme with antioxidant properties that is responsible for the reduction of cellular quinones. We hypothesized that CFB increases NQO1 activity, which in turn enhances the conversion of NAPQI back to the parent APAP. This could explain the decreases in APAP covalent binding and glutathione depletion produced by CFB without affecting APAP bioactivation to NAPQI. Administration of CFB (500 mg/kg, i.p.) to male CD-1 mice for 5 or 10 days increased NQO1 protein and activity levels. To evaluate the capacity of NQO1 to reduce NAPQI back to APAP, we utilized a microsomal activating system. Cytochrome P450 enzymes present in microsomes bioactivate APAP to NAPQI, which binds the electrophile trapping agent, N-acetyl cysteine (NAC). We analyzed the formation of APAP-NAC metabolite in the presence of human recombinant NQO1. Results indicate that NQO1 is capable of reducing NAPQI. The capacity of NQO1 to amelioriate APAP toxicity was then evaluated in primary hepatocytes. Primary hepatocytes isolated from mice dosed with CFB are resistant to APAP toxicity. These hepatocytes were also exposed to ES936, a high affinity, irreversible inhibitor of NQO1 in the presence of APAP. Concentrations of ES936 that resulted in over 94% inhibition of NQO1 activity did not increase the susceptibility of hepatocytes from CFB treated mice to APAP. Whereas NQO1 is mechanistically capable of reducing NAPQI, CFB-mediated hepatoprotection does not appear to be dependent upon enhanced expression of NQO1.

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Peroxisome proliferators protect against paracetamol hepatotoxicity in mice

Cited by 33 publications

References 6 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

Induction of Hepatic Transporters Multidrug Resistance-Associated Proteins (Mrp) 3 and 4 by Clofibrate Is Regulated by Peroxisome Proliferator-Activated Receptor α

Role of NAD(P)H:quinone oxidoreductase 1 in clofibrate-mediated hepatoprotection from acetaminophen

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