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  1. Artikel ; Online: NFATC2IP is a mediator of SUMO-dependent genome integrity.

    Cho, Tiffany / Hoeg, Lisa / Setiaputra, Dheva / Durocher, Daniel

    Genes & development

    2024  Band 38, Heft 5-6, Seite(n) 233–252

    Abstract: The post-translational modification of proteins by SUMO is crucial for cellular viability and mammalian development in part due to the contribution of SUMOylation to genome duplication and repair. To investigate the mechanisms underpinning the essential ... ...

    Abstract The post-translational modification of proteins by SUMO is crucial for cellular viability and mammalian development in part due to the contribution of SUMOylation to genome duplication and repair. To investigate the mechanisms underpinning the essential function of SUMO, we undertook a genome-scale CRISPR/Cas9 screen probing the response to SUMOylation inhibition. This effort identified 130 genes whose disruption reduces or enhances the toxicity of TAK-981, a clinical-stage inhibitor of the SUMO E1-activating enzyme. Among the strongest hits, we validated and characterized NFATC2IP, an evolutionarily conserved protein related to the fungal Esc2 and Rad60 proteins that harbors tandem SUMO-like domains. Cells lacking NFATC2IP are viable but are hypersensitive to SUMO E1 inhibition, likely due to the accumulation of mitotic chromosome bridges and micronuclei. NFATC2IP primarily acts in interphase and associates with nascent DNA, suggesting a role in the postreplicative resolution of replication or recombination intermediates. Mechanistically, NFATC2IP interacts with the SMC5/6 complex and UBC9, the SUMO E2, via its first and second SUMO-like domains, respectively. AlphaFold-Multimer modeling suggests that NFATC2IP positions and activates the UBC9-NSMCE2 complex, the SUMO E3 ligase associated with SMC5/SMC6. We conclude that NFATC2IP is a key mediator of SUMO-dependent genomic integrity that collaborates with the SMC5/6 complex.
    Mesh-Begriff(e) Cell Cycle Proteins/metabolism ; DNA Damage ; Sumoylation ; Ubiquitin-Protein Ligases/metabolism ; Humans ; Genomic Instability/genetics
    Chemische Substanzen Cell Cycle Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; NFATC2IP protein, human
    Sprache Englisch
    Erscheinungsdatum 2024-04-17
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 806684-x
    ISSN 1549-5477 ; 0890-9369
    ISSN (online) 1549-5477
    ISSN 0890-9369
    DOI 10.1101/gad.350914.123
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: The use of PD-1 functional knockout rats to study idiosyncratic adverse reactions to nevirapine.

    Cho, Tiffany / Hayes, Anthony / Henderson, Jeffrey T / Uetrecht, Jack

    Toxicological sciences : an official journal of the Society of Toxicology

    2024  

    Abstract: Idiosyncratic drug reactions (IDRs) are associated with significant patient morbidity/mortality and lead to considerable drug candidate attrition in drug development. Their idiosyncratic nature makes the study of IDRs difficult. In particular, nevirapine ...

    Abstract Idiosyncratic drug reactions (IDRs) are associated with significant patient morbidity/mortality and lead to considerable drug candidate attrition in drug development. Their idiosyncratic nature makes the study of IDRs difficult. In particular, nevirapine is associated with a relatively high risk of serious skin rash and liver injury. We previously found that nevirapine causes a similar skin rash in female Brown Norway rats, but these animals do not develop significant liver injury. Programmed cell death protein-1 (PD-1) is an immune checkpoint involved in immune tolerance, and anti-PD-1 antibodies have been used to treat cancer. However, they increase the risk of liver injury caused by co-administered drugs. We found that PD-1-/- mice are more susceptible to drug-induced liver injury, but PD-1-/- mice are not a good model for all drugs. In particular, they do not develop a skin rash when treated with nevirapine, at least in part because they lack the sulfotransferase in their skin that forms the reactive metabolite responsible for the rash. Therefore, we developed a PD-1 mutant (PD-1m/m) rat, with an excision in the ligand-binding domain of PD-1, to test whether nevirapine would cause a more serious skin rash in these animals. The PD-1m/m rat was based on a Sprague Dawley background, which has a lower incidence of skin rash than Brown Norway rats. The treated PD-1m/m rats developed more severe liver injury than PD-1-/- mice, but in contrast to expectations, they did not develop a skin rash. Functional knockouts provide a unique tool to study the mechanisms of IDRs.
    Sprache Englisch
    Erscheinungsdatum 2024-05-15
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 1420885-4
    ISSN 1096-0929 ; 1096-6080
    ISSN (online) 1096-0929
    ISSN 1096-6080
    DOI 10.1093/toxsci/kfae058
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: The development and characterization of a CRISPR/Cas9-mediated PD-1 functional knockout rat as a tool to study idiosyncratic drug reactions.

    Cho, Tiffany / Wierk, Antonia / Gertsenstein, Marina / Rodgers, Christopher E / Uetrecht, Jack / Henderson, Jeffrey T

    Toxicological sciences : an official journal of the Society of Toxicology

    2024  Band 198, Heft 2, Seite(n) 233–245

    Abstract: Idiosyncratic drug reactions are rare but serious adverse drug reactions unrelated to the known therapeutic properties of the drug and manifest in only a small percentage of the treated population. Animal models play an important role in advancing ... ...

    Abstract Idiosyncratic drug reactions are rare but serious adverse drug reactions unrelated to the known therapeutic properties of the drug and manifest in only a small percentage of the treated population. Animal models play an important role in advancing mechanistic studies examining idiosyncratic drug reactions. However, to be useful, they must possess similarities to those seen clinically. Although mice currently represent the dominant mammalian genetic model, rats are advantageous in many areas of pharmacologic study where their physiology can be examined in greater detail and is more akin to that seen in humans. In the area of immunology, this includes autoimmune responses and susceptibility to diabetes, in which rats more accurately mimic disease states in humans compared with mice. For example, oral nevirapine treatment can induce an immune-mediated skin rash in humans and rats, but not in mice due to the absence of the sulfotransferase required to form reactive metabolites of nevirapine within the skin. Using CRISPR-mediated gene editing, we developed a modified line of transgenic rats in which a segment of IgG-like ectodomain containing the core PD-1 interaction motif containing the native ligand and therapeutic antibody domain in exon 2 was deleted. Removal of this region critical for mediating PD-1/PD-L1 interactions resulted in animals with an increased immune response resulting in liver injury when treated with amodiaquine.
    Mesh-Begriff(e) Humans ; Rats ; Mice ; Animals ; Nevirapine/toxicity ; Nevirapine/metabolism ; Programmed Cell Death 1 Receptor/metabolism ; CRISPR-Cas Systems ; Models, Animal ; Liver/metabolism ; Drug-Related Side Effects and Adverse Reactions ; Mammals/metabolism
    Chemische Substanzen Nevirapine (99DK7FVK1H) ; Programmed Cell Death 1 Receptor
    Sprache Englisch
    Erscheinungsdatum 2024-01-16
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 1420885-4
    ISSN 1096-0929 ; 1096-6080
    ISSN (online) 1096-0929
    ISSN 1096-6080
    DOI 10.1093/toxsci/kfae003
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Testing Possible Risk Factors for Idiosyncratic Drug-Induced Liver Injury Using an Amodiaquine Mouse Model and Co-treatment with 1-Methyl-d-Tryptophan or Acetaminophen.

    Cho, Tiffany / Kok, Lie Yun / Uetrecht, Jack

    ACS omega

    2021  Band 6, Heft 7, Seite(n) 4656–4662

    Abstract: Idiosyncratic drug reactions are unpredictable adverse reactions. Although most such adverse reactions appear to be immune mediated, their exact mechanism(s) remain elusive. The idiosyncratic drug reaction most associated with serious consequences is ... ...

    Abstract Idiosyncratic drug reactions are unpredictable adverse reactions. Although most such adverse reactions appear to be immune mediated, their exact mechanism(s) remain elusive. The idiosyncratic drug reaction most associated with serious consequences is idiosyncratic drug-induced liver injury (IDILI). We have developed a mouse model of amodiaquine (AQ)-induced liver injury that reflects the clinical characteristics of IDILI in humans. This was accomplished by impairing immune tolerance by using PD-1
    Sprache Englisch
    Erscheinungsdatum 2021-02-07
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ISSN 2470-1343
    ISSN (online) 2470-1343
    DOI 10.1021/acsomega.0c05352
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Response to the Letter to the Editor Concerning the Article "Rotenone Increases Isoniazid Toxicity but Does Not Cause Liver Injury: Implications for the Hypothesis That Inhibition of the Mitochondrial Electron Transport Chain Is a Common Mechanism of Idiosyncratic Drug-Induced Liver Injury" by Bernard Fromenty.

    Cho, Tiffany / Uetrecht, Jack

    Chemical research in toxicology

    2019  Band 33, Heft 1, Seite(n) 5–6

    Mesh-Begriff(e) Chemical and Drug Induced Liver Injury ; Electron Transport ; Humans ; Isoniazid ; Rotenone
    Chemische Substanzen Rotenone (03L9OT429T) ; Isoniazid (V83O1VOZ8L)
    Sprache Englisch
    Erscheinungsdatum 2019-12-17
    Erscheinungsland United States
    Dokumenttyp Letter ; Comment
    ZDB-ID 639353-6
    ISSN 1520-5010 ; 0893-228X
    ISSN (online) 1520-5010
    ISSN 0893-228X
    DOI 10.1021/acs.chemrestox.9b00436
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: Liver Injury Caused by Green Tea Extract in PD-1

    Cho, Tiffany / Wang, Xijin / Yeung, Karen / Cao, Yanshan / Uetrecht, Jack

    Chemical research in toxicology

    2021  Band 34, Heft 3, Seite(n) 849–856

    Abstract: Idiosyncratic drug-induced liver injury (IDILI) is an idiosyncratic drug reaction that is specific to an individual and can lead to liver failure and even death. The mechanism of IDILI remains poorly understood, but most IDILI appears to be immune- ... ...

    Abstract Idiosyncratic drug-induced liver injury (IDILI) is an idiosyncratic drug reaction that is specific to an individual and can lead to liver failure and even death. The mechanism of IDILI remains poorly understood, but most IDILI appears to be immune-mediated. We have developed the first validated animal model by using a PD-1
    Mesh-Begriff(e) Animals ; Catechin/chemistry ; Catechin/pharmacology ; Chemical and Drug Induced Liver Injury/immunology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Immune Tolerance/drug effects ; Liver/drug effects ; Liver/immunology ; Liver/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Plant Extracts/chemistry ; Plant Extracts/pharmacology ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/deficiency ; Programmed Cell Death 1 Receptor/immunology ; Tea/chemistry
    Chemische Substanzen Pdcd1 protein, mouse ; Plant Extracts ; Programmed Cell Death 1 Receptor ; Tea ; Catechin (8R1V1STN48)
    Sprache Englisch
    Erscheinungsdatum 2021-02-22
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639353-6
    ISSN 1520-5010 ; 0893-228X
    ISSN (online) 1520-5010
    ISSN 0893-228X
    DOI 10.1021/acs.chemrestox.0c00485
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel ; Online: The Putative Drosophila TMEM184B Ortholog Tmep Ensures Proper Locomotion by Restraining Ectopic Firing at the Neuromuscular Junction.

    Cho, Tiffany S / Beigaitė, Eglė / Klein, Nathaniel E / Sweeney, Sean T / Bhattacharya, Martha R C

    Molecular neurobiology

    2022  Band 59, Heft 4, Seite(n) 2605–2619

    Abstract: TMEM184B is a putative seven-pass membrane protein that promotes axon degeneration after injury. TMEM184B mutation causes aberrant neuromuscular architecture and sensory and motor behavioral defects in mice. The mechanism through which TMEM184B causes ... ...

    Abstract TMEM184B is a putative seven-pass membrane protein that promotes axon degeneration after injury. TMEM184B mutation causes aberrant neuromuscular architecture and sensory and motor behavioral defects in mice. The mechanism through which TMEM184B causes neuromuscular defects is unknown. We employed Drosophila melanogaster to investigate the function of the closely related gene, Tmep (CG12004), at the neuromuscular junction. We show that Tmep is required for full adult viability and efficient larval locomotion. Tmep mutant larvae have a reduced body contraction rate compared to controls, with stronger deficits in females. In recordings from body wall muscles, Tmep mutants show substantial hyperexcitability, with many postsynaptic potentials fired in response to a single stimulation, consistent with a role for Tmep in restraining synaptic excitability. Additional branches and satellite boutons at Tmep mutant neuromuscular junctions are consistent with an activity-dependent synaptic overgrowth. Tmep is expressed in endosomes and synaptic vesicles within motor neurons, suggesting a possible role in synaptic membrane trafficking. Using RNAi knockdown, we show that Tmep is required in motor neurons for proper larval locomotion and excitability, and that its reduction increases levels of presynaptic calcium. Locomotor defects can be rescued by presynaptic knockdown of endoplasmic reticulum calcium channels or by reducing evoked release probability, further suggesting that excess synaptic activity drives behavioral deficiencies. Our work establishes a critical function for Tmep in the regulation of synaptic transmission and locomotor behavior.
    Mesh-Begriff(e) Animals ; Drosophila/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/metabolism ; Larva/metabolism ; Locomotion/genetics ; Mice ; Neuromuscular Junction/metabolism ; Presynaptic Terminals/metabolism ; Synaptic Transmission/physiology
    Chemische Substanzen Drosophila Proteins
    Sprache Englisch
    Erscheinungsdatum 2022-02-02
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 645020-9
    ISSN 1559-1182 ; 0893-7648
    ISSN (online) 1559-1182
    ISSN 0893-7648
    DOI 10.1007/s12035-022-02760-3
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel ; Online: How Reactive Metabolites Induce an Immune Response That Sometimes Leads to an Idiosyncratic Drug Reaction.

    Cho, Tiffany / Uetrecht, Jack

    Chemical research in toxicology

    2017  Band 30, Heft 1, Seite(n) 295–314

    Abstract: Little is known with certainty about the mechanisms of idiosyncratic drug reactions (IDRs); however, there is substantive evidence that reactive metabolites are involved in most, but not all, IDRs. In addition, evidence also suggests that most IDRs are ... ...

    Abstract Little is known with certainty about the mechanisms of idiosyncratic drug reactions (IDRs); however, there is substantive evidence that reactive metabolites are involved in most, but not all, IDRs. In addition, evidence also suggests that most IDRs are immune mediated. That raises the question of how reactive metabolites induce an immune response that can lead to an IDR. The dominant hypotheses are the hapten and danger hypotheses. These are complementary hypotheses: a reactive metabolite can act as a hapten to produce neoantigens, and it can also cause cell damage leading to the release of danger-associated molecular pattern molecules that activate antigen presenting cells. Both are required for an immune response. In addition, drugs may induce an immune response through inflammasome activation. We have found examples in which the ability to activate inflammasomes differentiated drugs that cause IDRs from similar drugs that do not. There are other hypotheses that do not involve an immune mechanism such as mitochondrial injury and bile salt export pump (BSEP) inhibition. With some possible exceptions, these hypotheses are unlikely to be able to completely explain IDRs. However, some types of mitochondrial injury or BSEP inhibition could produce danger signals. The major mechanism that protects us from IDRs appears to be immune tolerance. Consistent with this hypothesis, we used checkpoint inhibition to develop the first animal model of idiosyncratic drug-induced liver injury that has the same characteristics as the idiosyncratic injury in humans. This was accomplished by treating Pd-1
    Mesh-Begriff(e) Animals ; Drug-Related Side Effects and Adverse Reactions/immunology ; Drug-Related Side Effects and Adverse Reactions/metabolism ; Humans ; Immune Tolerance ; Pharmaceutical Preparations/metabolism ; Risk Factors
    Chemische Substanzen Pharmaceutical Preparations
    Sprache Englisch
    Erscheinungsdatum 2017--17
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 639353-6
    ISSN 1520-5010 ; 0893-228X
    ISSN (online) 1520-5010
    ISSN 0893-228X
    DOI 10.1021/acs.chemrestox.6b00357
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  9. Artikel ; Online: Rotenone Increases Isoniazid Toxicity but Does Not Cause Significant Liver Injury: Implications for the Hypothesis that Inhibition of the Mitochondrial Electron Transport Chain Is a Common Mechanism of Idiosyncratic Drug-Induced Liver Injury.

    Cho, Tiffany / Wang, Xijin / Uetrecht, Jack

    Chemical research in toxicology

    2019  Band 32, Heft 7, Seite(n) 1423–1431

    Abstract: Idiosyncratic drug reactions (IDRs) significantly increase the risk of failure in drug development. The major IDR leading to drug candidate failure is idiosyncratic drug-induced liver injury (IDILI). Although most evidence suggests that IDRs are mediated ...

    Abstract Idiosyncratic drug reactions (IDRs) significantly increase the risk of failure in drug development. The major IDR leading to drug candidate failure is idiosyncratic drug-induced liver injury (IDILI). Although most evidence suggests that IDRs are mediated by the immune system, there are other hypotheses, such as mitochondrial dysfunction. Many pharmaceutical companies routinely screen for mitochondrial toxicity in an attempt to "derisk" drug candidates. However, the basic hypothesis has never been rigorously tested. A major assay used for this screening involves measurement of inhibition of the mitochondrial electron transport chain. One study found that the combination of rotenone and isoniazid, which inhibit mitochondrial complex I and II, respectively, were synergistic in causing hepatocyte toxicity in vitro and suggested the combination of another drug that inhibited complex I would increase the risk of isoniazid-induced liver injury in patients. We tested this hypothesis in vivo where wild-type and PD-1-/- mice administered anti-CTLA-4, our impaired immune tolerance mouse model, were given 0.02% (w/v) rotenone in water or 0.1%, 0.05%, and 0.01% (w/w) rotenone alone or in combination with isoniazid in food. The cotreatment led to lethality in 100% of the animals receiving 0.1% rotenone and 0.2% isoniazid and 83% of the animals cotreated with 0.05% rotenone and 0.2% isoniazid in food. Nevertheless, there was no significant increase in GLDH or histological evidence of liver injury. No signs of toxicity were observed in any of the mice given rotenone or isoniazid alone. Even though inhibition of the mitochondrial electron transport chain did not lead to significant liver toxicity, it could provide danger signals that promote immune-mediated liver injury. However, rotenone did not significantly increase the liver injury induced by isoniazid in our impaired immune tolerance model. Overall, we conclude that inhibition of the mitochondrial electron transport chain is not a significant mechanism of IDILI.
    Mesh-Begriff(e) Animals ; Chemical and Drug Induced Liver Injury/etiology ; Drug Synergism ; Electron Transport/drug effects ; Electron Transport Complex I/antagonists & inhibitors ; Electron Transport Complex II/antagonists & inhibitors ; Enzyme Inhibitors/toxicity ; Female ; Isoniazid/toxicity ; Liver/drug effects ; Mice, Inbred C57BL ; Mitochondria/drug effects ; Rotenone/toxicity
    Chemische Substanzen Enzyme Inhibitors ; Rotenone (03L9OT429T) ; Electron Transport Complex II (EC 1.3.5.1) ; Electron Transport Complex I (EC 7.1.1.2) ; Isoniazid (V83O1VOZ8L)
    Sprache Englisch
    Erscheinungsdatum 2019-06-28
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639353-6
    ISSN 1520-5010 ; 0893-228X
    ISSN (online) 1520-5010
    ISSN 0893-228X
    DOI 10.1021/acs.chemrestox.9b00116
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  10. Artikel ; Online: Use of an animal model to test whether non-alcoholic fatty liver disease increases the risk of idiosyncratic drug-induced liver injury.

    Mak, Alastair / Cho, Tiffany / Uetrecht, Jack

    Journal of immunotoxicology

    2018  Band 15, Heft 1, Seite(n) 90–95

    Abstract: Clinical evidence suggests that most idiosyncratic drug-induced liver injury (IDILI) is immune-mediated. The danger hypothesis suggests that liver injury and inflammation would increase the risk of an immune response leading to IDILI. Therefore, a ... ...

    Abstract Clinical evidence suggests that most idiosyncratic drug-induced liver injury (IDILI) is immune-mediated. The danger hypothesis suggests that liver injury and inflammation would increase the risk of an immune response leading to IDILI. Therefore, a reasonable hypothesis would be that an underlying chronic liver disease such as non-alcoholic steatohepatitis (NASH) would increase the risk of developing IDILI due to inflammation and release of danger signals from damaged cells. In order to test this hypothesis, mice were fed a methionine-/choline-deficient (MCD) diet that produces a consistent NASH phenotype, along with amodiaquine (AQ) - a drug known to cause IDILI in humans. This study employed both wild-type C57BL/6 mice and PD-1
    Mesh-Begriff(e) Amodiaquine ; Animals ; Antibodies, Blocking/administration & dosage ; Chemical and Drug Induced Liver Injury/immunology ; Choline Deficiency ; Disease Models, Animal ; Female ; Granzymes ; Humans ; Inflammation/immunology ; Liver/drug effects ; Liver/immunology ; Methionine/deficiency ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Non-alcoholic Fatty Liver Disease/immunology ; Programmed Cell Death 1 Receptor/genetics ; Risk
    Chemische Substanzen Antibodies, Blocking ; Pdcd1 protein, mouse ; Programmed Cell Death 1 Receptor ; Amodiaquine (220236ED28) ; Methionine (AE28F7PNPL) ; Granzymes (EC 3.4.21.-) ; Gzmb protein, mouse (EC 3.4.21.-)
    Sprache Englisch
    Erscheinungsdatum 2018-05-17
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2205064-4
    ISSN 1547-6901 ; 1547-691X
    ISSN (online) 1547-6901
    ISSN 1547-691X
    DOI 10.1080/1547691X.2018.1467982
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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