Prediction of drug‐induced liver injury using keratinocytes

Hirashima, Rika; Itoh, Tomoo; Tukey, Robert H.; Fujiwara, Ryoichi

doi:10.1002/jat.3435

Cited by 12 publications

(4 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The keratinocytes used in this study were prepared as previously described ( 63 ), with minor modifications. Skin tissue was isolated from 1- or 2-day-old mice and incubated for 15–18 h at 4 ° C in CnT-PR medium (CELLnTEC; Bern, Switzerland) supplemented with antibiotic–antimycotic mixed solution and 5 mg/mL dispase (Wako Pure Chemical, Osaka, Japan).…”

Section: Methodsmentioning

confidence: 99%

HLA-B*57:01-dependent intracellular stress in keratinocytes triggers dermal hypersensitivity reactions to abacavir

Kazaoka,

Fujimori,

Yamada

et al. 2024

PNAS Nexus

View full text Add to dashboard Cite

Specific human leukocyte antigen (HLA) polymorphisms combined with certain drug administration strongly correlate with skin eruption. Abacavir hypersensitivity, which is strongly associated with HLA-B*57:01, is one of the most representative examples. Conventionally, HLA transmits immunological signals via interactions with T-cell receptors on the cell surface. This study focused on HLA-mediated intracellular reactions in keratinocytes that might determine the onset of skin immunotoxicity by drug treatments. Abacavir exposure resulted in keratinocytes expressing HLA-B*57:01 exhibiting endoplasmic reticulum (ER) stress responses, such as immediate calcium release into the cytosol and enhanced HSP70 expression. In contrast, keratinocytes expressing HLA-B*57:03 (closely related to HLA-B*57:01) did not show these changes. This indicated that HLA-B*57:01 has a specific intracellular response to abacavir in keratinocytes in the absence of lymphocytes. Furthermore, abacavir exposure in HLA-B*57:01-expressing keratinocytes elevated the expression of cytokines/chemokines such as IFN-γ, IL-1β, and CCL27, and induced T-lymphoblast migration. These effects were suppressed by ER stress relief using 4-phenylbutyrate. HLA-B*57:01-transgenic mice also exhibited ER stress in epidermal areas following abacavir administration, and abacavir-induced skin toxicity was attenuated by the administration of 4-phenylbutyrate. Moreover, abacavir bound to HLA-B*57:01 within cells and its exposure led to HLA-B*57:01 protein aggregation and interaction with molecular chaperones in the ER of keratinocytes. Our results underscore the importance of HLA-mediated intracellular stress responses in understanding the onset of HLA-B*57:01-mediated abacavir hypersensitivity. We provide the possibility that the intracellular behavior of HLA is crucial for determining the onset of drug eruptions.

show abstract

Section: Methodsmentioning

confidence: 99%

HLA-B*57:01-dependent intracellular stress in keratinocytes triggers dermal hypersensitivity reactions to abacavir

Kazaoka,

Fujimori,

Yamada

et al. 2024

PNAS Nexus

View full text Add to dashboard Cite

show abstract

“…Different hepatotoxic compounds have been shown to induce the expression of genes related to the immune and inflammatory response, such as S100A8, S100A9, NALP3, IL-1 β and RAGE in both hepatocytes 417 and primary human keratinocytes 418 . Furthermore, it has been observed that the basal expression and induction of IL-1 β in keratinocytes after exposure to hepatotoxic drugs can be a tool to identify individuals at high risk of iDILI 418 .…”

Section: Future Perspectivesmentioning

confidence: 99%

Preclinical models of idiosyncratic drug-induced liver injury (iDILI): Moving towards prediction

Segovia-Zafra

Zeo-Sánchez

Lopez‐Gómez

et al. 2021

Acta Pharmaceutica Sinica B

View full text Add to dashboard Cite

Idiosyncratic drug-induced liver injury (iDILI) encompasses the unexpected harms that prescription and non-prescription drugs, herbal and dietary supplements can cause to the liver. iDILI remains a major public health problem and a major cause of drug attrition. Given the lack of biomarkers for iDILI prediction, diagnosis and prognosis, searching new models to predict and study mechanisms of iDILI is necessary. One of the major limitations of iDILI preclinical assessment has been the lack of correlation between the markers of hepatotoxicity in animal toxicological studies and clinically significant iDILI. Thus, major advances in the understanding of iDILI susceptibility and pathogenesis have come from the study of well-phenotyped iDILI patients. However, there are many gaps for explaining all the complexity of iDILI susceptibility and mechanisms. Therefore, there is a need to optimize preclinical human in vitro models to reduce the risk of iDILI during drug development. Here, the current experimental models and the future directions in iDILI modelling are thoroughly discussed, focusing on the human cellular models available to study the pathophysiological mechanisms of the disease and the most used in vivo animal iDILI models. We also comment about in silico approaches and the increasing relevance of patient-derived cellular models.

show abstract

“…The use of patient-derived keratinocytes would also be an interesting approach to identify risk factors associated with liver injury related to immune-mediated cutaneous reactions [66]. Recent data suggest that DILI-associated genes are involved in the onset and progression of drug-induced skin toxicity and keratinocytes and hepatocytes may share similar responsiveness to hepatotoxic drugs [67].…”

Section: Causality Assessment Scales Strengths Limitationsmentioning

confidence: 99%

Critical Review of Gaps in the Diagnosis and Management of Drug-Induced Liver Injury Associated with Severe Cutaneous Adverse Reactions

Paz

Niu

Segovia-Zafra

et al. 2021

JCM

View full text Add to dashboard Cite

Drug-induced liver injury (DILI) encompasses the unexpected damage that drugs can cause to the liver. DILI may develop in the context of an immunoallergic syndrome with cutaneous manifestations, which are sometimes severe (SCARs). Nevirapine, allopurinol, anti-epileptics, sulfonamides, and antibiotics are the most frequent culprit drugs for DILI associated with SCARs. Interestingly, alleles HLA-B*58:01 and HLA-A*31:01 are associated with both adverse reactions. However, there is no consensus about the criteria used for the characterization of liver injury in this context, and the different thresholds for DILI definition make it difficult to gain insight into this complex disorder. Moreover, current limitations when evaluating causality in patients with DILI associated with SCARs are related to the plethora of causality assessment methods and the lack of consensual complementary tools. Finally, the management of this condition encompasses the treatment of liver and skin injury. Although the use of immunomodulant agents is accepted for SCARs, their role in treating liver injury remains controversial. Further randomized clinical trials are needed to test their efficacy and safety to address this complex entity. Therefore, this review aims to identify the current gaps in the definition, diagnosis, prognosis, and management of DILI associated with SCARs, proposing different strategies to fill in these gaps.

show abstract

Prediction of drug‐induced liver injury using keratinocytes

Cited by 12 publications

References 58 publications

HLA-B*57:01-dependent intracellular stress in keratinocytes triggers dermal hypersensitivity reactions to abacavir

HLA-B*57:01-dependent intracellular stress in keratinocytes triggers dermal hypersensitivity reactions to abacavir

Preclinical models of idiosyncratic drug-induced liver injury (iDILI): Moving towards prediction

Critical Review of Gaps in the Diagnosis and Management of Drug-Induced Liver Injury Associated with Severe Cutaneous Adverse Reactions

Contact Info

Product

Resources

About