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Hepatotoxicity Related to Anti-tuberculosis Drugs: Mechanisms and Management.

ABSTRACT: Development of idiosyncratic hepatotoxicity is an intricate process involving both concurrent as well as sequential events determining the direction of the pathways, degree of liver injury and its outcome. Decades of clinical observation have identified a number of drug and host related factors that are associated with an increased risk of antituberculous drug-induced hepatotoxicity, although majority of the studies are retrospective with varied case definitions and sample sizes. Investigations on genetic susceptibility to hepatotoxicity have so far focused on formation and accumulation reactive metabolite as well as factors that contribute to cellular antioxidant defense mechanisms and the environment which can modulate the threshold for hepatocyte death secondary to oxidative stress. Recent advances in pharmacogenetics have promised the development of refined algorithms including drug, host and environmental risk factors that allow better tailoring of medications based on accurate estimates of risk-benefit ratio. Future investigations exploring the pathogenesis of hepatotoxicity should be performed using human tissue and samples whenever possible, so that the novel findings can be translated readily into clinical applications.

SUBMITTER: Ramappa V

PROVIDER: S-EPMC3940184 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Hepatotoxicity Related to Anti-tuberculosis Drugs: Mechanisms and Management.

Ramappa Vidyasagar V Aithal Guruprasad P GP

Journal of clinical and experimental hepatology 20121220 1

Development of idiosyncratic hepatotoxicity is an intricate process involving both concurrent as well as sequential events determining the direction of the pathways, degree of liver injury and its outcome. Decades of clinical observation have identified a number of drug and host related factors that are associated with an increased risk of antituberculous drug-induced hepatotoxicity, although majority of the studies are retrospective with varied case definitions and sample sizes. Investigations ...[more]

PMID: 25755470

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Project description:Background: Tuberculosis (TB) remains a major public health problem, especially in developing countries, with 1.5 million deaths annually worldwide. Antibiotics are commonly used in the treatment of bacterial infections. As with most drugs, antibiotic treatment can also alter host metabolism, leading to adverse side-effects. Antibiotics can also interfere with the immune system, indirectly through the disturbance of the body’s microbiota or directly by modulating the functions of immune cells. It is therefore important to understand how antibiotic treatment modulates immune cell functions. Here we aim to evaluate the impact of first-line anti-TB drugs on the response of human macrophages infected with Mycobacterium tuberculosis (MTB). Results: Human macrophages were stimulated with heat-killed Mycobacterium tuberculosis (hk-MTB) and treated with isoniazid (INH), rifampicin (RIF), ethambutol, pyrazinamide (PZA) or amikacin (AMK). After 24h of treatment, RNA was collected and we characterized the genome-wide gene expression profiles of drug-treated cells by RNAseq. 556, 752 and 7 genes were differentially expressed in hk-MTB-stimulated macrophages upon RIF, PZA and EMB treatment respectively, whereas in uninfected macrophages, 448 and 11 genes were differentially expressed upon RIF and PZA treatment respectively. No genes were differentially expressed upon INH and AMK treatment. We classified all modulated genes by performing gene-set enrichment analysis. The gene set regulated by PZA in infected macrophages was significantly enriched for genes involved in Integral to lumenal side of endoplasmic reticulum membrane, Cytokine-mediated signaling pathway or Interferon-gamma-mediated signaling pathway. In hk-MTB-stimulated macrophages treated by RIF, we found an enrichment in Endoplasmic reticulum unfolded protein response, NADP binding or Lipid metabolic process. Conclusions: Our results highlight the importance to understand how antibiotic treatment modulates macrophage (Mφ) functions, and more generally, how it impacts the host immune response.

Dataset Information

Hepatotoxicity Related to Anti-tuberculosis Drugs: Mechanisms and Management.

Publications

Hepatotoxicity Related to Anti-tuberculosis Drugs: Mechanisms and Management.

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