Toxicoproteomic Profiling of hPXR Transgenic Mice Treated with Rifampicin and Isoniazid

Cells. 2020 Jul 9;9(7):1654. doi: 10.3390/cells9071654.


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.

Keywords: anemia; antitubercular therapy; cytochrome P450; drug-induced liver injury; heme biosynthesis; hypercoagulability; iron–sulfur cluster; pellagra; vitamin B3; vitamin B6.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / toxicity*
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Cytochrome P-450 Enzyme System / metabolism
  • Heme / metabolism
  • Homocysteine / metabolism
  • Iron-Sulfur Proteins / metabolism
  • Isoniazid / toxicity*
  • Liver / drug effects
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Niacinamide / metabolism
  • Oxidative Stress
  • Proteome / genetics
  • Proteome / metabolism*
  • Rifampin / toxicity*
  • Vitamin B 6 / metabolism


  • Antitubercular Agents
  • Iron-Sulfur Proteins
  • Proteome
  • Homocysteine
  • Niacinamide
  • Heme
  • Vitamin B 6
  • Cytochrome P-450 Enzyme System
  • Isoniazid
  • Rifampin