Tacrolimus Induced Organ Failure: Reversal by Activation of the Cytochrome P450-3a System

Tacrolimus is the cornerstone component of all immunosuppressive regimens. Despite its long record of use, very little is known about its acute toxicity syndrome. We describe five patients with acute organ failure, involving both native and transplanted organs, which was reversed by inducing the cytochrome P450-3A system. In all patients, the causative drug was stopped and phenytoin was given intravenously to accelerate tacrolimus metabolism. Within 24 h, tacrolimus trough levels fell daily at a significant level (p < 0.05) and all failed organs recovered their normal function within 48–72 h. Therefore, phenytoin metabolic induction appears to be a safe therapeutic option for patients with acute tacrolimus toxicity.

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Faculty Opinions recommendation of Knockout of cytochrome P450 3A yields new mouse models for understanding xenobiotic metabolism.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1094845.549770 ◽

2007 ◽

Author(s):

Erin Schuetz

Keyword(s):

Cytochrome P450 ◽

Mouse Models ◽

Xenobiotic Metabolism ◽

Cytochrome P450 3A

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Oxygen Economy of Cytochrome P450: What Is the Origin of the Mixed Functionality as a Dehydrogenase−Oxidase Enzyme Compared with Its Normal Function?

Journal of the American Chemical Society ◽

10.1021/ja0318737 ◽

2004 ◽

Vol 126 (16) ◽

pp. 5072-5073 ◽

Cited By ~ 48

Author(s):

Devesh Kumar ◽

Samuël P. de Visser ◽

Sason Shaik

Keyword(s):

Cytochrome P450 ◽

Normal Function ◽

Oxidase Enzyme

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Proteomic profiling of murine biliary-derived hepatic organoids and their capacity for drug disposition, bioactivation and detoxification

Archives of Toxicology ◽

10.1007/s00204-021-03075-3 ◽

2021 ◽

Author(s):

Lawrence Howell ◽

Rosalind E. Jenkins ◽

Stephen Lynch ◽

Carrie Duckworth ◽

B. Kevin Park ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Metabolism ◽

Rna Polymerase Ii ◽

Liver Tissue ◽

Drug Disposition ◽

Multiple Drug ◽

Proteomic Profiling ◽

Cytochrome P450 3A ◽

Drug Induced

AbstractHepatic organoids are a recent innovation in in vitro modeling. Initial studies suggest that organoids better recapitulate the liver phenotype in vitro compared to pre-existing proliferative cell models. However, their potential for drug metabolism and detoxification remains poorly characterized, and their global proteome has yet to be compared to their tissue of origin. This analysis is urgently needed to determine what gain-of-function this new model may represent for modeling the physiological and toxicological response of the liver to xenobiotics. Global proteomic profiling of undifferentiated and differentiated hepatic murine organoids and donor-matched livers was, therefore, performed to assess both their similarity to liver tissue, and the expression of drug-metabolizing enzymes and transporters. This analysis quantified 4405 proteins across all sample types. Data are available via ProteomeXchange (PXD017986). Differentiation of organoids significantly increased the expression of multiple cytochrome P450, phase II enzymes, liver biomarkers and hepatic transporters. While the final phenotype of differentiated organoids is distinct from liver tissue, the organoids contain multiple drug metabolizing and transporter proteins necessary for liver function and drug metabolism, such as cytochrome P450 3A, glutathione-S-transferase alpha and multidrug resistance protein 1A. Indeed, the differentiated organoids were shown to exhibit increased sensitivity to midazolam (10–1000 µM) and irinotecan (1–100 µM), when compared to the undifferentiated organoids. The predicted reduced activity of HNF4A and a resulting dysregulation of RNA polymerase II may explain the partial differentiation of the organoids. Although further experimentation, optimization and characterization is needed relative to pre-existing models to fully contextualize their use as an in vitro model of drug-induced liver injury, hepatic organoids represent an attractive novel model of the response of the liver to xenobiotics. The current study also highlights the utility of global proteomic analyses for rapid and accurate evaluation of organoid-based test systems.

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