rifampin and Chemical-and-Drug-Induced-Liver-Injury--Chronic

Tuberculosis (TB) remains a major global health burden. Antitubercular drugs (ATDs) such as isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol are used as first-line therapy in TB patients. Drug-induced liver injury is one of the common side effects that leads to the discontinuation of ATDs in TB patients. Therefore, this review discusses the molecular pathogenesis of ATDs induced liver injury. The biotransformation of INH, RIF, and PZA in the liver liberates several reactive intermediates, leading to peroxidation of the hepatocellular membrane and oxidative stress. INH + RIF administration decreased the expression of bile acid transporters such as the bile salt export pump and multidrug resistance-associated protein 2 and induced liver injury by sirtuin 1 and farnesoid X receptor pathway. INH inhibits the nuclear translocation of Nrf2 by interfering with its nuclear importer, karyopherin β1, thereby inducing apoptosis. INF + RIF treatments alter Bcl-2 and Bax homeostasis, mitochondrial membrane potential, and cytochrome c release, thereby triggering apoptosis. RIF administration enhances the expression of genes involved in fatty acid synthesis and hepatocyte fatty acid uptake (CD36). RIF induces the expression of peroxisome proliferator-activated receptor -γ and its downstream proteins and perilipin-2 by activating the pregnane X receptor in the liver to increase fatty infiltration into the liver. ATDs administration induces oxidative stress, inflammation, apoptosis, cholestasis, and lipid accumulation in the liver. However, ATDs toxic potentials are not elaborately studied at the molecular level in clinical samples. Therefore, future studies are warranted to explore ATDs induced liver injuries at the molecular level in clinical samples whenever possible.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Humans; Isoniazid; Pyrazinamide; Rifampin

Currently, most cases of active tuberculosis in the United States are a result of activation of latent tuberculosis infection. In this article, the history of the epidemiology of tuberculosis and latent tuberculosis infection is reviewed. Previous and current recommendations for screening and treatment for latent tuberculosis during pregnancy and the postpartum period are discussed. A review of the literature regarding postpartum and antepartum treatment is included. Finally, the question of whether antepartum or postpartum treatment is the most beneficial is discussed.

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury, Chronic; Female; Hispanic or Latino; Humans; Isoniazid; Mass Screening; Patient Compliance; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Prenatal Diagnosis; Rifampin; Tuberculosis; United States; Withholding Treatment

In this study, we aimed to determine whether asiatic acid (AA) exerts any therapeutic effects on rifampicin (RFP)- and isoniazid (INH)-induced liver injury and elucidate the underlying mechanisms. Briefly, liver injury in mice was induced via RFP and INH administration. We investigated the effects and potential action mechanisms of AA on liver injury using transcriptomics, metabolomics and various examinations. We found that AA significantly ameliorated the pathological changes in liver tissues and decreased the transaminase activity, inflammation and oxidative stress damage. Transcriptomics revealed 147 differentially expressed genes (DEGs) between the AA and model groups that were enriched in metabolic and mitogen-activated protein kinase (MAPK) signalling pathways. Metabolomics revealed 778 differentially expressed metabolites between the AA and model groups. Furthermore, integrated transcriptomics and metabolomics analyses revealed strong correlations between DEGs and differentially expressed metabolites and indicated that AA regulates the sphingolipid metabolism by inhibiting the expression of delta 4-desaturase, sphingolipid 1. Experimental results confirmed that AA inhibited the MAPK signalling pathway. In summary, AA inhibits inflammation and oxidative stress damage by regulating the sphingolipid metabolism pathway and blocking the MAPK signalling pathway, thereby relieving the RFP/INH-induced liver injury.

Topics: Animals; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Inflammation; Isoniazid; Liver; Mice; Mitogen-Activated Protein Kinases; Rifampin

Bergenin (BER), a natural component of polyphenols, has a variety of pharmacological activities, especially in improving drug metabolism, reducing cholestasis, anti-oxidative stress and inhibiting inflammatory responses. The aim of this study was to investigate the effects of BER on liver injury induced by isonicotinic acid hydrazide (INH) and rifampicin (RIF) in mice. The mice model of liver injury was established with INH (100 mg/kg)+RIF (100 mg/kg), and then different doses of BER were used to intervene. The pathological morphology and biochemical indicators of mice were detected. Meanwhile, RNA sequencing was performed to screen the differentially expressed genes and signaling pathways. Finally, critical differentially expressed genes were verified by qRT-PCR and Western blot. RNA sequencing results showed that 707 genes were significantly changed in the INH+RIF group compared with the Control group, and 496 genes were significantly changed after the BER intervention. These differentially expressed genes were mainly enriched in the drug metabolism, bile acid metabolism, Nrf2 pathway and TLR4 pathway. The validation results of qRT-PCR and Western blot were consistent with the RNA sequencing. Therefore, BER alleviated INH+RIF-induced liver injury in mice. The mechanism of BER improving INH+RIF-induced liver injury was related to regulating drug metabolism enzymes, bile acid metabolism, Nrf2 pathway and TLR4 pathway.

Topics: Animals; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Isoniazid; Liver; Mice; NF-E2-Related Factor 2; Rifampin; Toll-Like Receptor 4

Ritonavir (RTV), a pharmacoenhancer used in anti-HIV regimens, can induce liver damage. RTV is primarily metabolized by cytochrome P450 3A4 (CYP3A4) in the liver. HNF4A antisense RNA 1 (HNF4A-AS1) and HNF1A antisense RNA 1 (HNF1A-AS1) are long noncoding RNAs that regulate the expression of pregnane X receptor (PXR) and CYP3A4. This study investigated the role and underlying mechanisms of HNF4A-AS1 and HNF1A-AS1 in RTV-induced hepatotoxicity. HNF4A-AS1 and HNF1A-AS1 were knocked down by small hairpin RNAs in Huh7 and HepG2 cells. Lactate dehydrogenase and reactive oxygen species assays were performed to assess RTV-induced hepatotoxicity. Chromatin immunoprecipitation quantitative real-time polymerase chain reaction was used to detect PXR enrichment and histone modifications in the CYP3A4 promoter. HNF4A-AS1 knockdown increased PXR and CYP3A4 expression and exacerbated RTV-induced cytotoxicity, whereas HNF1A-AS1 knockdown generated the opposite phenotype. Mechanistically, enrichment of PXR and trimethylation of histone 3 lysine 4 (H3K4me3) in the CYP3A4 promoter was increased, and trimethylation of histone 3 lysine 27 (H3K27me3) was decreased after HNF4A-AS1 knockdown. However, PXR and H3K4me3 enrichment decreased after HNF1A-AS1 knockdown. Alterations in RTV-induced hepatotoxicity caused by decreasing HNF4A-AS1 or HNF1A-AS1 were reversed by knockdown or overexpression of PXR. Increased susceptibility to RTV-induced liver injury caused by the PXR activator rifampicin was attenuated by HNF4A-AS1 overexpression or HNF1A-AS1 knockdown. Taken together, these results revealed that HNF4A-AS1 and HNF1A-AS1 modulated RTV-induced hepatotoxicity by regulating CYP3A4 expression, primarily by affecting the binding of PXR and histone modification status in the CYP3A4 promoter. SIGNIFICANCE STATEMENT: HNF4A-AS1 and HNF1A-AS1, transcribed separately from neighboring antisense genes of the human transcription factor genes

Topics: Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury, Chronic; Cytochrome P-450 CYP3A; Hepatocyte Nuclear Factor 1; Hepatocyte Nuclear Factor 4; Histones; Humans; Liver Neoplasms; Lysine; Receptors, Steroid; Rifampin; Ritonavir; RNA, Antisense; RNA, Long Noncoding

Topics: Animals; Apoptosis; Chemical and Drug Induced Liver Injury, Chronic; Cytoprotection; Endoplasmic Reticulum Stress; Hep G2 Cells; Hepatocytes; Humans; Liver; Male; Mice; Mice, Inbred ICR; Multidrug Resistance-Associated Protein 2; Phenylbutyrates; Protective Agents; Rifampin; Signal Transduction; Ubiquitination

Anti-tuberculosis drugs-induced liver injury may be associated with the hepatic farnesoid X receptor (FXR). However, the relationship between isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) coadministration-induced liver injury and FXR has not been clarified. The purpose of this study was to clarify the role of FXR in HRZE-induced liver injury. To measure indices of liver injury, blood samples were collected from clinical tuberculosis patients who had taken HRZE for approximately two months; in these patients serum total bile acids were increased, while other hepatic biochemical indexes showed no significant changes. When Wistar rats were orally administered isoniazid (30 or 60 mg/kg) + rifampicin (45 or 90 mg/kg) + pyrazinamide (150 or 300 mg/kg) + ethambutol (75 or 150 mg/kg) in combination for 15 days, the expression and function of FXR was up-regulated, and hepatic bile acids were decreased. However, following 30 days of HRZE treatment the expression and function of FXR was down-regulated and bile acids accumulated in the liver, suggestive of hepatotoxicity. Treatment of HepaRG cells with HRZE lead to time- and dose- dependent cytotoxicity, with the expression of FXR up-regulated in early stage, but down-regulated with prolonged HRZE treatment, consistent with the results of animal experiments. In summary, HRZE may upregulate FXR with short-term administration, but more prolonged treatment appears to suppress FXR function, resulting in hepatic bile acid accumulation.

Topics: Animals; Antitubercular Agents; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Ethambutol; Isoniazid; Liver; Pyrazinamide; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Rifampin

The protective effect of phloridzin (PHL) and its potential mechanism were examined in mice with liver injury induced by isoniazid (INH) and rifampicin (RFP). The mice were randomly divided into normal control group, model group, low (80 mg/kg), medium (160 mg/kg) and high (320 mg/kg) phloridzin-treated groups. After 28 d treatment, blood and liver tissue were collected and analysed. The results revealed that PHL regulated liver function related indicators and reduced the pathological tissue damage, indicating that PHL significantly alleviated the liver injury. Furthermore, the level of CYP450 enzyme, the expression of CYP3A4, CYP2E1, heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and protein were inhibited by PHL. These results indicated that PHL exerts a protecting effect against liver injury induced by combination of RFP and INH. The potential mechanisms may be concerned with the activation of Nrf2/HO-1 signaling pathway containing its key antioxidant enzymes and regulation of CYP3A4 and CYP2E1.

Topics: Animals; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP3A; Heme Oxygenase-1; Isoniazid; Liver; Mice; NF-E2-Related Factor 2; Oxidative Stress; Phlorhizin; Rifampin

Rifampicin (RFP)-induced cholestatic liver injury is characterized by impaired hepatic bile acid (BA) transport. Bile salt efflux pump (BSEP) and Na+/taurocholate cotransporter (NTCP) are the major BA transporters. However, little is known about the mechanisms underlying these transporters.. The role of tanshinone IIA (TAN IIA) in preventing RFP-induced liver injury was evaluated in vitro and in vivo, based on the regulatory mechanism of nuclear factor erythroid 2-related factor 2 (NRF2)-BSEP/NTCP signalling. The epigenetic induction of NRF2 by TAN IIA was investigated as well as the influence on BSEP and NTCP transcriptional activation and NRF2 DNA-binding ability.. TAN IIA strongly induced BSEP and NTCP expression in hepatocytes. NRF2 knockdown abrogated the induction. We found two NRF2 binding sites on the human BSEP promoter, called musculoaponeurotic fibrosarcoma recognition elements (MAREs), and one MARE on the NTCP promoter. Human BSEP and NTCP promoter luciferase reporter gene plasmids were stimulated by NRF2. Mutations of the predicted MAREs abolished NRF2 transcriptional activation. TAN IIA induced the expression of ten-eleven translocation 2 (TET2) to mediate the demethylation of NRF2, which promoted NRF2 DNA-binding on the BSEP and NTCP promoters and their transcriptional activation. Finally, in vivo, Nrf2 played an important role in RFP-induced liver injury (more serious liver injury in Nrf2-/- mice), and TAN IIA prevented it.. These results indicate that NRF2 regulates the target transporters BSEP and NTCP, depending on the DNA demethylation by TET2. Pharmacological activation of NRF2 by TAN IIA may be beneficial for RFP-induced liver injury.

Topics: Abietanes; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; Bile Acids and Salts; Chemical and Drug Induced Liver Injury, Chronic; Epigenesis, Genetic; Female; HEK293 Cells; Hepatocytes; Humans; Liver; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Organic Anion Transporters, Sodium-Dependent; Rifampin; Symporters

The present study aims to investigate the protective effects of Dendrobine and its underlying mechanisms on liver injury induced by isoniazid (INH) and rifampicin (RIF). A mouse model of liver injury was induced by intragastrically administration of 100 mg/kg INH and 100 mg/kg RIF for 14 days. The mice were intragastrically administrated with Dendrobine (50, 100, and 200 mg/kg) before the administration of INH and RIF. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. Oxidative stress markers including glutathione, superoxide dismutase, and malondialdehyde in the liver were measured and liver histopathological examinations were performed. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot were applied to determine the mRNA and protein expressions, respectively. Luciferase reporter assay was used to evaluate the interactions between miR-295-5p and CYP1A2. Dendrobine significantly decreased serum ALT and AST and inhibited the liver index and ameliorated the liver histological changes induced by INH and RIF. Besides, Dendrobine also regulated oxidative stress status in the liver by the regulation of CYP1A2. Moreover, mmu-miR-295-5p was identified to target CYP1A2 and to regulate the expression of CYP1A2. In summary, Dendrobine ameliorated INH and RIF induced mouse liver injury by miR-295-5p-mediated CYP1A2 expression.

Topics: Alanine Transaminase; Alkaloids; Animals; Anti-Bacterial Agents; Aspartate Aminotransferases; Cell Line; Chemical and Drug Induced Liver Injury, Chronic; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Isoniazid; Liver; Mice, Inbred C57BL; Mice, Inbred ICR; MicroRNAs; Oxidative Stress; Rifampin