Inverse gene expression patterns for macrophage activating hepatotoxicants and peroxisome proliferators in rat liver

McMillian, Michael; Nie, Alex; Parker, J. Brandon; Leone, Angelique; Kemmerer, Matthias; Bryant, Stewart; Herlich, Judy; Yieh, Lynn; Bittner, Anton; Liu, Xuejun; Wan, Jackson; Johnson, Mark D.

doi:10.1016/j.bcp.2004.01.029

Cited by 57 publications

(40 citation statements)

References 88 publications

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“…39 For instance, PPARs are known to be activated by different CysLTs antagonists [40][41][42] and to produce a generalized suppressive effect on activation of immune cells. 43 Involvement of PPARs, rather than CysLT 1 , in those in vivo effects of CysLT 1 antagonists would be consistent with our finding that two activators of PPARa, 8S-HETE and ETYA, inhibited release of both IL-12 and IL-10 from LPSstimulated BM-DCs.…”

Section: Discussionsupporting

confidence: 79%

Leukotrienes modulate cytokine release from dendritic cells

et al. 2005

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Summary Leukotriene B4 (LTB4) and cysteinyl leukotrienes (CysLTs) are known as potent mediators of inflammation, whereas their role in the regulation of adaptive immunity remains poorly characterized. Dendritic cells (DCs) are specialized antigen‐presenting cells, uniquely capable to initiate primary immune responses. We have found that zymosan, but not lipopolysaccharide (LPS) stimulates murine bone marrow‐derived dendritic cells (BM‐DCs) to produce large amounts of CysLTs and LTB4 from endogenous substrates. A selective inhibitor of leukotriene synthesis MK886 as well as an antagonist of the high affinity LTB4 receptor (BLT1) U‐75302 slightly inhibited zymosan‐, but not LPS‐stimulated interleukin (IL)‐10 release from BM‐DCs. In contrast, U‐75302 increased zymosan‐stimulated release of IL‐12 p40 by ∼23%. Pre‐treatment with transforming growth factor‐β1 enhanced both stimulated leukotriene synthesis and the inhibitory effect of U‐75302 and MK886 on IL‐10 release from DCs. Consistent with the effects of leukotriene antagonists, exogenous LTB4 enhanced LPS‐stimulated IL‐10 release by ∼39% and inhibited IL‐12 p40 release by ∼22%. Both effects were mediated by the BLT1 receptor. Ligands of the high affinity CysLTs receptor (CysLT1), MK‐571 and LTD4 had little or no effect on cytokine release. Agonists of the nuclear LTB4 receptor peroxisome proliferator‐activated receptor‐α, 8(S)‐hydroxyeicosatetraenoic acid and 5,8,11,14‐eicosatetraynoic acid, inhibited release of both IL‐12 p40 and IL‐10. Our results indicate that both autocrine and paracrine leukotrienes may modulate cytokine release from DCs, in a manner that is consistent with previously reported T helper 2‐polarizing effects of leukotrienes.

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Section: Discussionsupporting

confidence: 79%

Leukotrienes modulate cytokine release from dendritic cells

et al. 2005

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“…A recent study applied toxicogenomics profiling to differentiate chemical reagents known to cause hepatotoxicity and oxidative stress into three subcategories: macrophage activators (MA), peroxisome proliferators (PP), and oxidative stressors/reactive metabolites (OS/RM) (McMillian et al, 2004a(McMillian et al, , 2004b(McMillian et al, , 2005. A supervised training/testing approach was used to differentiate MA, PP, and OS/RM gene transcriptional signature patterns in rat liver.…”

Section: Discussionmentioning

confidence: 99%

“…Gene expression responses were selected that best separated the training set samples from all other treated and control samples. Transcription factors that distinguished the OS/RM class, such as Gst mu1 and heat shock proteins, are related to the Keap1-Nrf2-ARE signaling pathway (McMillian et al, 2004a(McMillian et al, , 2004b(McMillian et al, , 2005, which is believed to be a response to oxidative or electrophilic stress and promote cell survival (Talalay et al, 2003;Dinkova-Kostova et al, 2005;Shen et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…In our study, 20 out of 30 of most up-regulated genes from both CBZ-and PHN-treated mice overlap with the list of genes used as the gene set used to distinguish oxidative stressors that belong to the OS/RM class (McMillian et al, 2004a(McMillian et al, 2004b and also overlap with the list of genes involved in the Keap1-Nrf2-ARE signaling pathway (Kwak et al, 2003). This suggests that CBZ and PHN or their metabolites are responsible for an oxidative stress response that disrupts the Keap1-Nrf2 complex and serves as the common mechanism shared by both drugs.…”

Section: Discussionmentioning

confidence: 99%

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Changes in Gene Expression Induced by Carbamazepine and Phenytoin: Testing the Danger Hypothesis

Uetrecht

2008

Journal of Immunotoxicology

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The aromatic anticonvulsants carbamazepine (CBZ) and phenytoin (PHN) are associated with a relatively high incidence of idiosyncratic drug reactions (IDRs). If biomarkers could be found that would predict the risk that a drug candidate would cause IDRs it would significantly decrease the risks associated with drug development. The IDRs associated with CBZ and PHN appear to be immune-mediated. The Danger Hypothesis posits that for something to induce an immune response, it must cause some type of cell damage that ultimately causes up-regulation of co-stimulatory molecules on antigen-presenting cells; without this, the response will be immune tolerance. If the Danger Hypothesis is correct, the ability of a drug or its reactive metabolite to induce cell damage or stress may be related to its risk of causing IDRs. In a parallel study reported elsewhere, we found that major metabolites of these two drugs: 3-OH-CBZ and 4-OH-PHN can be oxidized by peroxidases to phenoxyl free radicals, which could cause oxidative stress by redox cycling. In this study using mRNA microarrays, we found that CBZ and PHN treatment induced changes in mRNA expression in mice. Many of the changes were in genes related to Keap1-Nrf2-ARE signaling pathways and enzymes involved in responding Abbreviations: AP-1, activator protein 1; PPARα, peroxisome proliferator-activated receptor α; ARE, antioxidant response element; CBZ, carbamazepine; Cp, crossing point; GST, glutathione S-transferase; Gapdh, glyceraldehydes-3-phosphate dehydrogenase; HSP, heat shock protein; IDR, idiosyncratic drug reaction; Keap1, Kelch-like ECH-associated protein 1; MA, Macrophage activators; NF-κB, nuclear factor κB; Nrf2, nuclear factor-erythroid 2-related factor 2; 3-OH-CBZ, 3-hydroxycarbamazepine; 4-OH-PHN, 4-hydroxyphenytoin; OS/RM, oxidative stressors/reactive metabolites; PCR, polymerase chain reaction; PHN, phenytoin, 5,5-diphenylhydantoin; PP, peroxisome proliferators; ROS, reactive oxygen species; Stat-3, signal transducers and activators of transcription-3; UDPG, uridine diphosphoglucose.Current address for Wei Lu: Biotransformation, Drug Safety and Metabolism, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426.Address correspondence to Jack Uetrecht, MD, PhD, Leslie Dan Faculty of Pharmacy, Room 1010, University of Toronto, 144 College Street, Toronto, Ontario, Canada M5S 3M2; e-mail jack.uetrecht@utoronto.ca to oxidant stressors and reactive metabolites such as glutathione transferase and heat shock proteins. The similar patterns of genes induced by these two drugs are consistent with the clinical observation that those two drugs exhibit cross-sensitivity. These findings are consistent with the induction of cell stress by CBZ and PHN, most likely due to reactive metabolites. Such changes may represent a danger signal and represent a biomarker of the potential that a drug will cause IDRs; however, different drugs likely cause cell stress by different mechanisms and, therefore, the biomarkers for other drugs would likely be different.

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“…[1,[6][7][8] [9] TGx has also contributed to the mechanistic understanding of some toxicity issues, for example, explaining rodent-specific carcinogenesis associated with peroxisome proliferator-activated receptor α agonists. [10] However, TGx has not been widely incorporated into drug discovery pipelines. The rapid growth in TGx publications has declined over the last decade, as did submissions to the Voluntary eXploratory Data Submission program of the FDA.…”

Section: The Advance Of Toxicogenomicsmentioning

confidence: 99%