Drug-induced liver injury is a major safety issue in anti-tuberculosis (TB) chemotherapy. The long- term goal of our research is to improve the safety profile of medication with anti-TB drugs. The objective of this application is to determine the mechanism of liver injury associated with rifampicin and isoniazid co-therapy. Extensive studies have been conducted previously to investigate the liver injury caused by rifampicin and isoniazid in mice or rats; however, none of these studies mimicked the hepatotoxicity in humans. Species differences between rodents and humans in responding to rifampicin and/or isoniazid are expected. Pregnane X receptor (PXR) is a transcription factor regulating a gene network involved in the metabolism of xenobiotics and endobiotics. The ability of chemicals to activate PXR is species- dependent. Rifampicin is a human specific PXR activator, which strongly activates human PXR, but has a very weak effect on mouse PXR. To overcome the species differences in ligand-dependent PXR activation, we generated a PXR-humanized mouse model. By using these PXR-humanized mice, we noted that rifampicin and isoniazid-induced liver injury is human PXR-dependent. However, rifampicin- mediated PXR activation does not alter isoniazid metabolism. By using a metabolomic approach, we found that rifampicin and isoniazid co-treatment caused protoporphyrin IX (PP-IX) accumulation, specifically in liver, and this is human PXR-dependent. PP-IX is an intermediate in porphyrin synthesis, and has been shown to be hepatotoxic in previous studies. Based upon our preliminary data and previous reports, we hypothesize that rifampicin and isoniazid co-treatment disturbs porphyrin synthesis, and the accumulation of PP-IX in liver mediates the hepatotoxicity. To test our hypothesis, we will pursue the following two specific aims: (1) identify the toxic mediator(s) in the liver injury caused by rifampicin and isoniazid co-therapy. Our working hypothesis is that the accumulation of PP-IX in liver is the key mediator of the hepatotoxicity caused by rifampicin and isoniazid co-therapy; and (2) determine the human PXR-dependent pathway(s) responsible for the hepatotoxicity in rifampicin and isoniazid co- therapy. Our working hypothesis is that human PXR-mediated up-regulation of aminolevulinic acid synthase 1, the rate-limiting enzyme in porphyrin synthesis in liver, is critical in the hepatotoxicity caused by rifampicin and isoniazid co-therapy. The results from these studies are expected to provide a new paradigm for the mechanistic understanding of rifampicin and isoniazid-induced hepatotoxicity. Novel strategies, based upon human PXR, aminolevulinic acid synthase 1, and PP-IX, can be developed to predict, prevent, and treat the liver injury caused by rifampicin and isoniazid co-therapy.

Public Health Relevance

Rifampicin and isoniazid co-therapy frequently causes liver injury, and even liver failure. This proposed project will provide a novel mechanistic understanding of the liver injury induced by rifampicin and isoniazid co-therapy, which can be applied to predict, prevent, and treat this toxic event.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
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Serrano, Jose
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University of Pittsburgh
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Bao, Yifan; Ma, Xiaochao; Rasmussen, Theodore P et al. (2018) Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury. Curr Pharmacol Rep 4:171-181
Zhu, Junjie; Wang, Pengcheng; Li, Feng et al. (2018) CYP1A1 and 1B1-mediated metabolic pathways of dolutegravir, an HIV integrase inhibitor. Biochem Pharmacol 158:174-184
Piekos, Stephanie C; Chen, Liming; Wang, Pengcheng et al. (2018) Consequences of Phenytoin Exposure on Hepatic Cytochrome P450 Expression during Postnatal Liver Maturation in Mice. Drug Metab Dispos 46:1241-1250
Wang, Pengcheng; Sachar, Madhav; Guo, Grace L et al. (2018) Liver metabolomics in a mouse model of erythropoietic protoporphyria. Biochem Pharmacol 154:474-481
Wang, Pengcheng; Shehu, Amina I; Lu, Jie et al. (2017) Deficiency of N-acetyltransferase increases the interactions of isoniazid with endobiotics in mouse liver. Biochem Pharmacol 145:218-225
Wang, Pengcheng; Shehu, Amina I; Ma, Xiaochao (2017) The Opportunities of Metabolomics in Drug Safety Evaluation. Curr Pharmacol Rep 3:10-15
Sachar, Madhav; Ma, Xiaochao (2016) Role of ABCG2 in liver injury associated with erythropoietic protoporphyria. Hepatology 64:305
Sachar, Madhav; Li, Feng; Liu, Ke et al. (2016) Chronic Treatment with Isoniazid Causes Protoporphyrin IX Accumulation in Mouse Liver. Chem Res Toxicol 29:1293-7
Li, Feng; Wang, Pengcheng; Liu, Ke et al. (2016) A High Dose of Isoniazid Disturbs Endobiotic Homeostasis in Mouse Liver. Drug Metab Dispos 44:1742-1751
Wang, Pengcheng; Pradhan, Komal; Zhong, Xiao-Bo et al. (2016) Isoniazid metabolism and hepatotoxicity. Acta Pharm Sin B 6:384-392

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