Merrie Mosedale

University of North Carolina Health Care

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Paul B. Watkins

University of North Carolina at Chapel Hill

J. Scott Eaddy

University of North Carolina at Chapel Hill

Sharin E. Roth

Pharmaceutical Product Development (United States)

Manisha Nautiyal

University of North Carolina at Chapel Hill

Rachel J. Church

CSL (United States)

William J. Brock

Scientific Consulting Group

Kristina K. Wolf

BioNTech (Germany)

Natalie S. Holman

Eli Lilly (United States)

Brett A. Howell

Simulations Plus (United States)

Sean Hammond

University of Liverpool

Cooperative Institutions

University of North Carolina at Chapel Hill

Research Triangle Park Foundation

The Hamner Institutes for Health Sciences

Duke University

Triangle

University of North Carolina Health Care

University of California, San Diego

University of Liverpool

Acorda Therapeutics (United States)

Duke Medical Center

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Mitochondrial Overload and Incomplete Fatty Acid Oxidation Contribute to Skeletal Muscle Insulin Resistance

Cell Metabolism (2008)

Timothy R. Koves John R. Ussher Robert C. Noland Dorothy H. Slentz Merrie Mosedale

10.1016/j.cmet.2007.10.013

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Citations (1,830)

Neurexin-1α Contributes to Insulin-containing Secretory Granule Docking

Journal of Biological Chemistry (2012)

Merrie Mosedale Sonya Egodage Rei C. Calma Nai‐Wen Chi Steven Chessler

Neurexin

Granule (geology)

Secretory Vesicle

10.1074/jbc.m111.299081

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Citations (34)

Mechanisms of Drug‐induced Liver Injury

Paul B. Watkins Merrie Mosedale

Drug-induced liver injury (DILI) is typically divided into two categories: "intrinsic" and "idiosyncratic." Intrinsic DILI is dose-dependent and usually predictable. In contrast, idiosyncratic DILI is difficult to predict as it has a complex dose-response relationship, its onset is typically delayed, and it is often observed in only a small percentage of treated patients. Both intrinsic and idiosyncratic DILI involve some level of direct drug-induced stress or injury to liver cells through three major mechanisms: mitochondrial dysfunction, oxidative stress, and alterations in bile acid homeostasis. In some cases of idiosyncratic hepatocellular DILI, hepatocyte stress leads to an adaptive immune response that in combination with loss of immune tolerance is ultimately responsible for clinically important liver injury. Both properties intrinsic to the drug as well as host factors determine susceptibility to DILI. New cell culture, preclinical animal, and computational models hold promise for guiding an improved understanding and prediction of DILI.

Homeostasis

Liver cell

10.1002/9781119251316.ch28

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Citations (1)

Drug‐induced liver injury: Advances in mechanistic understanding that will inform risk management

Clinical Pharmacology & Therapeutics (2016)

Merrie Mosedale PB Watkins

Drug-induced liver injury (DILI) is a major public health problem. Intrinsic (dose-dependent) DILI associated with acetaminophen overdose is the number one cause of acute liver failure in the US. However, the most problematic type of DILI impacting drug development is idiosyncratic, occurring only very rarely among treated patients and often only after several weeks or months of treatment with the offending drug. Recent advances in our understanding of the pathogenesis of DILI suggest that three mechanisms may underlie most hepatocyte effects in response to both intrinsic and idiosyncratic DILI drugs: mitochondrial dysfunction, oxidative stress, and alterations in bile acid homeostasis. However, in some cases hepatocyte stress promotes an immune response that results in clinically important idiosyncratic DILI. This review discusses recent advances in our understanding of the pathogenesis of both intrinsic and idiosyncratic DILI as well as emerging tools and techniques that will likely improve DILI risk identification and management.

Acetaminophen

Pathogenesis

10.1002/cpt.564

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Citations (177)

Identification of Candidate Risk Factor Genes for Human Idelalisib Toxicity Using a Collaborative Cross Approach

Toxicological Sciences (2019)

Merrie Mosedale Yanwei Cai J. Scott Eaddy Robert W. Corty Manisha Nautiyal

Idelalisib is a phosphatidylinositol 3-kinase inhibitor highly selective for the delta isoform that has shown good efficacy in treating chronic lymphocytic leukemia and follicular lymphoma. In clinical trials, however, idelalisib was associated with rare, but potentially serious liver and lung toxicities. In this study, we used the Collaborative Cross (CC) mouse population to identify genetic factors associated with the drug response that may inform risk management strategies for idelalisib in humans. Eight male mice (4 matched pairs) from 50 CC lines were treated once daily for 14 days by oral gavage with either vehicle or idelalisib at a dose selected to achieve clinically relevant peak plasma concentrations (150 mg/kg/day). The drug was well tolerated across all CC lines, and there were no observations of overt liver injury. Differences across CC lines were seen in drug concentration in plasma samples collected at the approximate Tmax on study Days 1, 7, and 14. There were also small but statistically significant treatment-induced alterations in plasma total bile acids and microRNA-122, and these may indicate early hepatocellular stress required for immune-mediated hepatotoxicity in humans. Idelalisib treatment further induced significant elevations in the total cell count of terminal bronchoalveolar lavage fluid, which may be analogous to pneumonitis observed in the clinic. Genetic mapping identified loci associated with interim plasma idelalisib concentration and the other 3 treatment-related endpoints. Thirteen priority candidate quantitative trait genes identified in CC mice may now guide interrogation of risk factors for adverse drug responses associated with idelalisib in humans.

Idelalisib

10.1093/toxsci/kfz199

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Citations (22)

PPARγ coactivator-1α contributes to exercise-induced regulation of intramuscular lipid droplet programming in mice and humans

Journal of Lipid Research (2012)

Timothy R. Koves Lauren M. Sparks Jean‐Paul Kovalik Merrie Mosedale Ramamani Arumugam

Intramuscular accumulation of triacylglycerol, in the form of lipid droplets (LD), has gained widespread attention as a hallmark of metabolic disease and insulin resistance. Paradoxically, LDs also amass in muscles of highly trained endurance athletes who are exquisitely insulin sensitive. Understanding the molecular mechanisms that mediate the expansion and appropriate metabolic control of LDs in the context of habitual physical activity could lead to new therapeutic opportunities. Herein, we show that acute exercise elicits robust upregulation of a broad program of genes involved in regulating LD assembly, morphology, localization, and mobilization. Prominent among these was perilipin-5, a scaffolding protein that affects the spatial and metabolic interactions between LD and their surrounding mitochondrial reticulum. Studies in transgenic mice and primary human skeletal myocytes established a key role for the exercise-responsive transcriptional coactivator PGC-1α in coordinating intramuscular LD programming with mitochondrial remodeling. Moreover, translational studies comparing physically active versus inactive humans identified a remarkably strong association between expression of intramuscular LD genes and enhanced insulin action in exercise-trained subjects. These results reveal an intimate molecular connection between intramuscular LD biology and mitochondrial metabolism that could prove relevant to the etiology and treatment of insulin resistance and other disorders of lipid imbalance.

Lipid droplet

10.1194/jlr.p028910

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Citations (92)

Shedding Light on Drug-Induced Liver Injury: Activation of T Cells From Drug Naive Human Donors With Tolvaptan and a Hydroxybutyric Acid Metabolite

Toxicological Sciences (2020)

Sean Hammond Andrew Gibson Kanoot Jaruthamsophon Sharin E. Roth Merrie Mosedale

Exposure to tolvaptan is associated with a significant risk of liver injury in a small fraction of patients with autosomal dominant polycystic kidney disease. The observed delayed onset of liver injury of between 3 and 18 months after commencing tolvaptan treatment, along with rapid recurrence of symptoms following re-challenge is indicative of an adaptive immune attack. This study set out to assess the intrinsic immunogenicity of tolvaptan and pathways of drug-specific T-cell activation using in vitro cell culture platforms. Tolvaptan (n = 7), as well as oxybutyric (DM-4103, n = 1) and hydroxybutyric acid (DM-4107, n = 18) metabolite-specific T-cell clones were generated from tolvaptan naive healthy donor peripheral blood mononuclear cells. Tolvaptan and DM-4103 T-cell clones could also be activated with DM-4107, whereas T-cell clones originally primed with DM-4107 were highly specific to this compound. A signature cytokine profile (IFN-γ, IL-13, granzyme B, and perforin) for almost all T-cell clones was identified. Mechanistically, compound-specific T-cell clone activation was dependent on the presence of soluble drug and could occur within 4 h of drug exposure, ruling out a classical hapten mechanism. However, antigen processing dependence drug presentation was indicated in many T-cell clones. Collectively these data show that tolvaptan-associated liver injury may be attributable to an adaptive immune attack upon the liver, with tolvaptan- and metabolite-specific T cells identified as candidate effector cells in such etiology.

Tolvaptan

10.1093/toxsci/kfaa157

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Citations (9)

Differential Detergent Fractionation of Membrane Protein From Small Samples of Hepatocytes and Liver Tissue for Quantitative Proteomic Analysis of Drug Metabolizing Enzymes and Transporters

Journal of Pharmaceutical Sciences (2020)

Rani J. Qasem John K. Fallon Manisha Nautiyal Merrie Mosedale Philip C. Smith

Digitonin

Cell fractionation

Homogenization

Differential centrifugation

10.1016/j.xphs.2020.10.037

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Citations (9)

A Systems Biology Approach Utilizing a Mouse Diversity Panel Identifies Genetic Differences Influencing Isoniazid-Induced Microvesicular Steatosis

Carolina Digital Repository (University of North Carolina at Chapel Hill) (2014)

Rachel J. Church Hong Wu Merrie Mosedale Susan Sumner Wimal Pathmasiri

Steatosis

10.17615/a9en-vt15

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Citations (0)

Challenges and Solutions for Future Pharmacy Practice in the Era of Precision Medicine

American Journal of Pharmaceutical Education (2017)

Olivia M Dong Rachel Howard Rachel J. Church Mackenzie L. Cottrell Alan Forrest

As precision medicine research and its clinical applications continue to advance, it is critical for pharmacists to be involved in these developments to deliver optimal, tailored drug therapies for patients. To ensure pharmacists remain leaders in the field, the annual Pharmaceutical Sciences Conference convened by the University of North Carolina at Chapel Hill Eshelman School of Pharmacy focused on the role of pharmacy within precision medicine. This is a summary of the conference, highlighting the major challenges and solutions that will help advance individualized pharmacological methods within practice and research.

Chapel

Clinical Practice

10.5688/ajpe6652

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Citations (5)