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Uncovering the mechanism of troglitazone-mediated idiosyncratic drug-induced liver injury with individual-centric models.
Roux, Salomé; Cherradi, Sara; Duong, Hong Tuan.
Afiliação
  • Roux S; PredictCan Biotechnologies SAS, Biopôle Euromédecine, 1682 Rue de La Valsière, 34790, Grabels, France.
  • Cherradi S; PredictCan Biotechnologies SAS, Biopôle Euromédecine, 1682 Rue de La Valsière, 34790, Grabels, France.
  • Duong HT; PredictCan Biotechnologies SAS, Biopôle Euromédecine, 1682 Rue de La Valsière, 34790, Grabels, France. ht.duong@predictcan.com.
Arch Toxicol ; 98(11): 3875-3884, 2024 Nov.
Article em En | MEDLINE | ID: mdl-39105737
ABSTRACT
Idiosyncratic drug-induced liver injury is a rare and unpredictable event. Deciphering its initiating-mechanism is a hard task as its occurrence is individual dependent. Thus, studies that utilize models that are not individual-centric might drive to a general mechanistic conclusion that is not necessarily true. Here, we use the individual-centric spheroid model to analyze the initiating-mechanism of troglitazone-mediated iDILI risk. Individual-centric spheroid models were generated using a proprietary cell educating technology. These educated spheroids contain hepatocytes, hepatic stellate cells, activated monocyte-derived macrophages, and dendritic cells under physiological conditions. We show that phases 1 and 2 drug-metabolizing enzymes were induced in an individual-dependent manner. However, we did not observe any association of DEMs induction and troglitazone (TGZ)-mediated iDILI risk. We analyzed TGZ-mediated iDILI and found that a 44-year-old male showed iDILI risk that is associated with TGZ-mediated suppression of IL-12 expression by autologous macrophages and dendritic cells. We performed a rescue experiment and showed that treatment of spheroids from this 44-year-old male with TGZ and recombinant IL-12 suppressed iDILI risk. We confirmed the mechanism in another 31-year-old female with iDILI risk. We demonstrate here that individual-centric spheroid are versatile models that allow to predict iDILI risk and to analyze a direct effect of the drug on activated macrophages and dendritic cells to uncover the initiating-mechanism of iDILI occurrence. This model opens perspectives for a personalized strategy to mitigate iDILI risk.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células Dendríticas / Hepatócitos / Células Estreladas do Fígado / Doença Hepática Induzida por Substâncias e Drogas / Troglitazona / Macrófagos Limite: Adult / Female / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células Dendríticas / Hepatócitos / Células Estreladas do Fígado / Doença Hepática Induzida por Substâncias e Drogas / Troglitazona / Macrófagos Limite: Adult / Female / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article