High-Throughput Imaging of PPIX Using Confocal Microscopy

Brewer, Christopher T.; Low, Jonathan; Chen, Taosheng

doi:10.1007/978-1-4939-9195-2_11

Cited by 1 publication

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“…The human pregnane X receptor (hPXR) is implicated in the hepatotoxicity of pharmaceuticals [ 23 , 24 ] and herbal supplements [ 25 ]. This hepatotoxicity is associated with increased protoporphyrin IX (PPIX), which is a precursor to heme suitable for quantification via high-throughput fluorescence imaging [ 26 ]. The iron-dependent modulation of ferrochelatase (FECH) and aminolevulinic acid synthase 1 (ALAS1) is also driven by metabolites of isoniazid [ 27 ].…”

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confidence: 99%

Toxicoproteomic Profiling of hPXR Transgenic Mice Treated with Rifampicin and Isoniazid

Brewer

Kodali

et al. 2020

Cells

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Tuberculosis is a global health threat that affects millions of people every year, and treatment-limiting toxicity remains a considerable source of treatment failure. Recent reports have characterized the nature of hPXR-mediated hepatotoxicity and the systemic toxicity of antitubercular drugs. The antitubercular drug isoniazid plays a role in such pathologic states as acute intermittent porphyria, anemia, hepatotoxicity, hypercoagulable states (deep vein thrombosis, pulmonary embolism, or ischemic stroke), pellagra (vitamin B3 deficiency), peripheral neuropathy, and vitamin B6 deficiency. However, the mechanisms by which isoniazid administration leads to these states are unclear. To elucidate the mechanism of rifampicin- and isoniazid-induced liver and systemic injury, we performed tandem mass tag mass spectrometry-based proteomic screening of mPxr–/– and hPXR mice treated with combinations of rifampicin and isoniazid. Proteomic profiling analysis suggested that the hPXR liver proteome is affected by antitubercular therapy to disrupt [Fe–S] cluster assembly machinery, [2Fe–2S] cluster-containing proteins, cytochrome P450 enzymes, heme biosynthesis, homocysteine catabolism, oxidative stress responses, vitamin B3 metabolism, and vitamin B6 metabolism. These novel findings provide insight into the etiology of some of these processes and potential targets for subsequent investigations. Data are available via ProteomeXchange with identifier PXD019505.

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