Abstract
Co-therapy with rifampicin (RIF) and isoniazid (INH) used to treat tuberculosis in humans frequently causes liver injury. Here, using a pregnane X receptor (PXR)-humanized mouse model, we found that co-treatment with RIF and INH causes accumulation of the endogenous hepatotoxin protoporphyrin IX in the liver through PXR-mediated alteration of the heme biosynthesis pathway. These results provide insight into the mechanism of liver injury induced by co-treatment with these compounds and may lead to their safer use in the clinic.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Alanine Transaminase / blood
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Alkaline Phosphatase / blood
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Animals
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Antitubercular Agents / administration & dosage
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Antitubercular Agents / adverse effects*
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Antitubercular Agents / therapeutic use
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Chemical and Drug Induced Liver Injury / etiology*
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Chemical and Drug Induced Liver Injury / metabolism
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Chemical and Drug Induced Liver Injury / pathology
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Drug Therapy, Combination / adverse effects
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Heme / analysis
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Heme / biosynthesis
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Humans
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Isoniazid / administration & dosage
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Isoniazid / adverse effects*
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Isoniazid / therapeutic use
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Liver / chemistry
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Liver / drug effects
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Liver / metabolism
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Liver / pathology
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Male
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Mice
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Mice, Transgenic
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Pregnane X Receptor
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Protoporphyrins / analysis
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Protoporphyrins / biosynthesis
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Receptors, Steroid / drug effects*
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Receptors, Steroid / metabolism
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Receptors, Steroid / physiology
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Rifampin / administration & dosage
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Rifampin / adverse effects*
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Rifampin / therapeutic use
Substances
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Antitubercular Agents
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Pregnane X Receptor
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Protoporphyrins
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Receptors, Steroid
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Heme
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protoporphyrin IX
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Alanine Transaminase
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Alkaline Phosphatase
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Isoniazid
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Rifampin