Toxicoproteomic Profiling of hPXR Transgenic Mice Treated with Rifampicin and Isoniazid

Brewer, Christopher T.; Kodali, Kiran; Wu, Jing; Shaw, Timothy I.; Peng, Junmin; Chen, Taosheng

doi:10.3390/cells9071654

Cited by 8 publications

(6 citation statements)

References 99 publications

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“…This suggests that metabolomics can be used to evaluate and predict DILI. There are a few clinical and animal experiments using metabolomics to explore the toxic mechanism and biomarkers of ATB-DILI (20)(21)(22)(23)(24)(25). Nontargeted metabolomics found that 28 metabolites can be used as important distinguishing factors between ATB-DILI and non-ATB-DILI patients, and ATB-DILI affects the tricarboxylic acid cycle, arginine and proline metabolism, purine metabolism and pentose phosphate pathway (24).…”

Section: Introductionmentioning

confidence: 99%

Urine metabolomics and microbiome analyses reveal the mechanism of anti-tuberculosis drug-induced liver injury, as assessed for causality using the updated RUCAM: A prospective study

Wang

Wu²,

Zhang³

et al. 2022

Front. Immunol.

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BackgroundAnti-tuberculosis drug-induced liver injury (ATB-DILI) is one of the most common adverse reactions that brings great difficulties to the treatment of tuberculosis. Thus, early identification of individuals at risk for ATB-DILI is urgent. We conducted a prospective cohort study to analyze the urinary metabolic and microbial profiles of patients with ATB-DILI before drug administration. And machine learning method was used to perform prediction model for ATB-DILI based on metabolomics, microbiome and clinical data.MethodsA total of 74 new TB patients treated with standard first-line anti-TB treatment regimens were enrolled from West China Hospital of Sichuan University. Only patients with an updated RUCAM score of 6 or more were accepted in this study. Nontargeted metabolomics and microbiome analyses were performed on urine samples prior to anti-tuberculosis drug ingestion to screen the differential metabolites and microbes between the ATB-DILI group and the non-ATB-DILI group. Integrating electronic medical records, metabolomics, and microbiome data, four machine learning methods was used, including random forest algorithm, artificial neural network, support vector machine with the linear kernel and radial basis function kernel.ResultsOf all included patients, 69 patients completed follow-up, with 16 (23.19%) patients developing ATB-DILI after antituberculosis treatment. Finally, 14 ATB-DILI patients and 30 age- and sex-matched non-ATB-DILI patients were subjected to urinary metabolomic and microbiome analysis. A total of 28 major differential metabolites were screened out, involving bile secretion, nicotinate and nicotinamide metabolism, tryptophan metabolism, ABC transporters, etc. Negativicoccus and Actinotignum were upregulated in the ATB-DILI group. Multivariate analysis also showed significant metabolic and microbial differences between the non-ATB-DILI and severe ATB-DILI groups. Finally, the four models showed high accuracy in predicting ATB-DILI, with the area under the curve of more than 0.85 for the training set and 1 for the validation set.ConclusionThis study characterized the metabolic and microbial profile of ATB-DILI risk individuals before drug ingestion for the first time. Metabolomic and microbiome characteristics in patient urine before anti-tuberculosis drug ingestion may predict the risk of liver injury after ingesting anti-tuberculosis drugs. Machine learning algorithms provides a new way to predict the occurrence of ATB-DILI among tuberculosis patients.

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Section: Introductionmentioning

confidence: 99%

Urine metabolomics and microbiome analyses reveal the mechanism of anti-tuberculosis drug-induced liver injury, as assessed for causality using the updated RUCAM: A prospective study

Wang

Wu²,

Zhang³

et al. 2022

Front. Immunol.

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“…However, when used in combination, these two drugs produce different mechanisms of liver injury and the hepatotoxicity of the combination may be more frequent or severe than either drug alone. [ 5 ] It was believed that the metabolites acetylhydrazine and hydrazine contributed to the hepatotoxicity of INH. Subsequently, it was found that INH could induce immunologic liver injury and involve a cholestasis balance.…”

Section: Introductionmentioning

confidence: 99%

Exploration of the underlying mechanisms of isoniazid/rifampicin‐induced liver injury in mice using an integrated proteomics and metabolomics approach

Song

Tao

et al. 2022

J Biochem & Molecular Tox

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The hepatotoxic mechanism resulting from coadministration of isoniazid (INH) and rifampicin (RIF) are complex and studies remain inconclusive. To systematically explore the underlying mechanisms, an integrated mass‐based untargeted metabolomics and label‐free quantitative proteomics approach was used to clarify the mechanism of INH/RIF‐induced liver injury. Thirty male mice were randomly divided into three groups: control (receiving orally administered vehicle solution), INH (150 mg/kg) + RIF (300 mg/kg) orally administered for either 7 or 14 days, respectively. Serum was collected for the analysis of biochemical parameters and liver samples were obtained for mass spectrum‐based proteomics, metabolomics, and lipidomics analysis. Overall, 511 proteins, 31 metabolites, and 23 lipids were dysregulated and identified, and disordered biological pathways were identified. The network of integrated multiomics showed that glucose, lipid, and amino acid metabolism as well as energy metabolism were mainly dysregulated and led to oxidative stress, inflammation, liver steatosis, and cell death induced by INH and RIF. Coadministration of INH and RIF can induce liver injury by oxidative stress, inflammation, liver steatosis, and cell death, and the reduction in glutathione levels may play a critical role in these systematic changes and warrants further study.

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“…The anti-tuberculosis drug isoniazid plays an important role in pathological states like acute intermittent porphyria, anemia, hepatotoxicity, hypercoagulable state (deep vein thrombosis, pulmonary embolism or ischemic stroke), pellagra (vitamin В 3 deficiency), peripheral neuropathy, and vitamin В 6 deficiency (Brewer et al, 2020). Lee et al (2013) investigated the toxic effects of isoniazid on mice.…”

Section: Discussionmentioning

confidence: 99%

Histological and histochemical changes in the peripheral organs of the immune system of dogs in cases of isoniazid poisoning

Kotsyumbas

Vretsona

2021

Regul. Mech. Biosyst.

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Most publications on isoniazid poisoning in dogs are devoted to clinical diagnostics, treatment, and prevention of the disease. Histological and histochemical changes are not fully described, though they are important in assessing the toxic effects of isoniazid. Isoniazid is used to treat tuberculosis in humans. Dogs are hypersensitive to this drug. The article highlights the results of macroscopic, histological, and histochemical studies of the dogs’ lymph nodes and spleen in cases of isoniazid poisoning. A pathological examination of 19 corpses of dogs of different ages was performed, during which isoniazid poisoning was posthumously diagnosed, based on anamnesis, clinical signs, pathological autopsy, histological, and histochemical examination. Samples of lymph nodes and spleen were fixed in a 10% aqueous neutral formalin solution, Carnoy’s solution, and Bouin’s fixative. Histoсuts were prepared using a sled microtome and stained with hematoxylin and eosin. Staining was also performed according to the techniques suggested by McManus, Brachet, and Perls. The pathomorphological changes in lymph nodes and spleen were characterized by disorganization of vascular walls and connective tissue fibers of the stroma, dilatation of veins, their overflow with hemolyzed blood, and, in cases of the long clinical course, thrombosis of small vessels. Intravascular hemolysis of erythrocytes resulted in an excessive formation of hemosiderin. Histochemically, the spleen and lymph nodes showed a significant increase in the number of hemosiderophages in the spleen’s red and white pulp and the lymph nodes’ central sinuses and pulp cords. In the spleen, mucoid swelling and necrobiotic changes in the wall structures of the arterioles and arteries progressed with a narrowing of their lumen in dogs suffering from the long clinical course. Increased permeability of the microcirculatory tract vessels of the spleen and lymph nodes, transudate formation, and the destructive changes in the reticular skeleton accompanied hemodynamic violations. A sharp change in blood rheology caused the violation of trophism and metabolism in the immune system. Lymphoid elements of the lymph nodes and white pulp of the spleen were in a state of karyorrhexis and karyolysis. The morphological study of the immune system’s peripheral organs suggests that dogs poisoned by isoniazid demonstrate hemodynamic disorders, changes in the physicochemical properties of blood (hemolysis of erythrocytes and thrombosis). This is the basis of trophic disorders, metabolic malfunctions, and the development of dystrophic processes in all structural elements of the spleen and lymph nodes.

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Toxicoproteomic Profiling of hPXR Transgenic Mice Treated with Rifampicin and Isoniazid

Cited by 8 publications

References 99 publications

Urine metabolomics and microbiome analyses reveal the mechanism of anti-tuberculosis drug-induced liver injury, as assessed for causality using the updated RUCAM: A prospective study

Urine metabolomics and microbiome analyses reveal the mechanism of anti-tuberculosis drug-induced liver injury, as assessed for causality using the updated RUCAM: A prospective study

Exploration of the underlying mechanisms of isoniazid/rifampicin‐induced liver injury in mice using an integrated proteomics and metabolomics approach

Histological and histochemical changes in the peripheral organs of the immune system of dogs in cases of isoniazid poisoning

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