Induction of hepatic heme oxygenase-1 by diclofenac in rodents: role of oxidative stress and cytochrome P-450 activity

Cantoni, L; Valaperta, Rea; Ponsoda, Xavier; Castell, José V.; Barelli, Davide; Rizzardini, Milena; Mangolini, Alessandra; Hauri, Lisa; Villa, Pia

doi:10.1016/s0168-8278(03)00095-3

Cited by 55 publications

(29 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Adduct formation of protein with reactive metabolites (Miyamoto et al, 1997;Pumford et al, 1993) and hypersensitivity (Romano et al, 1994;Salama et al, 1991;Kretz-Rommel and Boelsterli, 1993) have been proposed as mechanisms for DF-induced idiosyncratic hepatotoxicity which is not well understood. Although transcriptional effects of DF on hepatocytes are not well characterized, a previous study showed that DF induced Hmox1 mRNA in rat liver and in rat primary hepatocytes at intensive doses: 300 μM for 3 h in vitro (Cantoni et al, 2003). This type of change was not observed in this study.…”

Section: Drugs Not Directly Toxic To Hepatocytes In Vivo or Rarely Tocontrasting

confidence: 74%

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

Suzuki¹,

Inoue²,

Matsushita³

et al. 2008

J of Applied Toxicology

View full text Add to dashboard Cite

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.

show abstract

Section: Drugs Not Directly Toxic To Hepatocytes In Vivo or Rarely Tocontrasting

confidence: 74%

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

Suzuki¹,

Inoue²,

Matsushita³

et al. 2008

J of Applied Toxicology

View full text Add to dashboard Cite

show abstract

“…Several mechanisms of DCLF-induced hepatotoxicity have been proposed, including metabolic and kinetic factors Aithal and Day, 2007;Daly et al, 2007), oxidative stress (Cantoni et al, 2003), and mitochondrial injury (Masubuchi et al, 2002;Lim et al, 2006;Lim et al, 2008;Siu et al, 2008). However, additional studies are required to determine the relevance of these mechanisms in vivo.…”

Section: B Diclofenac-induced Idiosyncratic Hepatotoxicitymentioning

confidence: 99%

Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models

et al. 2009

View full text Add to dashboard Cite

“…Thus, the pathogenesis of this low-incidence/high-severity DCLF hepatotoxicity is largely unknown. Several mechanisms have been proposed, including formation of reactive drug metabolites, oxidative stress (Cantoni et al, 2003), mitochondrial injury (Masubuchi et al, 2002), and immune-mediated hypersensitivity (Greaves et al, 2001). Experimental data supporting such mechanisms are incomplete, especially at the in vivo level (Boelsterli, 2003;Cantoni et al, 2003).…”

mentioning

confidence: 99%

Modest Inflammation Enhances Diclofenac Hepatotoxicity in Rats: Role of Neutrophils and Bacterial Translocation

Deng

Stachlewitz

Liguori

et al. 2006

J Pharmacol Exp Ther

136

View full text Add to dashboard Cite

Idiosyncratic adverse drug reactions (IADRs) represent an important human health problem, yet animal models for preclinical prediction of these reactions are lacking. Recent evidence in animals suggests that some IADRs arise from drug interaction with an inflammatory episode that renders the liver sensitive to injury. Diclofenac (DCLF) is one of those drugs for which the clinical use is limited by idiosyncratic liver injury. We tested the hypothesis that modest inflammation triggered in rats by a small dose of lipopolysaccharide (LPS) renders a nonhepatotoxic dose of DCLF injurious to liver. Cotreatment of rats with nonhepatotoxic doses of LPS and DCLF resulted in elevated serum alanine aminotransferase activity and liver histopathologic changes 6 h after DCLF administration. Neither LPS nor DCLF alone had such an effect. Gene array analysis of livers revealed a unique gene expression pattern in the LPS/DCLFcotreated group compared with groups given either agent alone. Antiserum-induced neutrophil (PMN) depletion in LPS/ DCLF-cotreated rats protected against liver injury, demonstrating a role for PMNs in the pathogenesis of this LPS/DCLF interaction. Gut sterilization of LPS/DCLF-treated rats did not protect against liver injury. In contrast, gut sterilization did attenuate liver injury caused by a large, hepatotoxic dose of DCLF, suggesting that hepatotoxicity induced by large doses of DCLF is caused in part by its ability to increase intestinal permeability to endotoxin or other bacterial products. These results demonstrate that inflammation-DCLF interaction precipitates hepatotoxicity in rats and raise the possibility of creating animal models that predict human IADRs.

show abstract

Induction of hepatic heme oxygenase-1 by diclofenac in rodents: role of oxidative stress and cytochrome P-450 activity

Cited by 55 publications

References 34 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

Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models

Modest Inflammation Enhances Diclofenac Hepatotoxicity in Rats: Role of Neutrophils and Bacterial Translocation

Contact Info

Product

Resources

About