Selected Pharmaceutical Excipient Prevent Isoniazid and Rifampicin Induced Hepatotoxicity

Shih, Tiffany Ting-Fang; Ho, Shan Chu; Hsiong, Cheng Huei; Huang, Tsai-Wang; Hu, Oliver Yoa Pu

doi:10.2174/1389200211314060008

Cited by 12 publications

(7 citation statements)

References 36 publications

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“…The study controls for other factors, such as plasma concentrations of isoniazid and rifampicin, and levels of other critical enzymes in AT-DILI, such as NAT2 and CYP2E1. Another CYP2E1 inhibitor, mannitol, has also proven to have a preventative effect on isoniazid- and rifampicin-mediated AT-DILI in mouse liver [60]. The effect of this CYP2E1 inhibitor shows that the CYP2E1 activity is essential for the development of AT-DILI.…”

Section: Specific Molecular Mechanisms Of Isoniazid/rifampicin-inducementioning

confidence: 99%

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

Bao

Rasmussen

et al. 2018

Curr Pharmacol Rep

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Purpose of this Review In order to combat the development of drug resistance, the clinical treatment of tuberculosis requires the combined use of several anti-tuberculosis (anti-TB) drugs, including isoniazid and rifampicin. Combinational treatment approaches are suggested by the World Health Organization (WHO) and are widely accepted throughout the world. Unfortunately, a major side effect of the treatment is the development of anti-tuberculosis drug-induced liver injury (AT-DILI). Many factors contribute to isoniazid- and rifampicin-mediated AT-DILI and genetic variations are among the most common factors. The purpose of this review is to provide information on genetic variations associated with isoniazid- and rifampicin-mediated AT-DILI. Recent Findings The genetic variations associated with AT-DILI have been identified in the genomic regions within or near genes encoding proteins in the following pathways: drug metabolizing enzymes (NAT2, CYP2E1, and GSTs), accumulation of bile acids, lipids, and heme metabolites (CYP7A1, BSEP, UGTs, and PXR), immune adaptation (HLAs and TNF-α), and oxidant challenge (TXNRD1, SOD1, BACH1, and MAFK). Summary The information summarized in this review considers the genetic bases of risk factors contributing to AT-DILI and provides information that may help for future studies. Some of the implicated genetic variations can be used in the design of genetic tests and serve as biomarkers for the prediction of isoniazid- and rifampicin-mediated AT-DILI risk in personalized medicine.

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Section: Specific Molecular Mechanisms Of Isoniazid/rifampicin-inducementioning

confidence: 99%

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

Bao

Rasmussen

et al. 2018

Curr Pharmacol Rep

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“…Two in vitro studies showed that rifampicin caused a direct toxic injury to rat hepatocytes [9, 10]. Several in vivo studies found that rifampicin plus isoniazid induced hepatocyte apoptosis in rodent animals [11–13]. The mechanism through which rifampicin induces liver injury remains obscure.…”

Section: Introductionmentioning

confidence: 99%

Rifampicin-Induced Hepatic Lipid Accumulation: Association with Up-Regulation of Peroxisome Proliferator-Activated Receptor γ in Mouse Liver

Huang

Zhang

et al. 2016

PLoS ONE

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Previous study found that rifampicin caused intrahepatic cholestasis. This study investigated the effects of rifampicin on hepatic lipid metabolism. Mice were orally administered with rifampicin (200 mg/kg) daily for different periods. Results showed that serum TG level was progressively reduced after a short elevation. By contrast, hepatic TG content was markedly increased in rifampicin-treated mice. An obvious hepatic lipid accumulation, as determined by Oil Red O staining, was observed in mice treated with rifampicin for more than one week. Moreover, mRNA levels of Fas, Acc and Scd-1, several key genes for fatty acid synthesis, were elevated in rifampicin-treated mice. In addition, the class B scavenger receptor CD36 was progressively up-regulated by rifampicin. Interestingly, hepatic SREBP-1c and LXR-α, two important transcription factors that regulate genes for hepatic fatty acid synthesis, were not activated by rifampicin. Instead, hepatic PXR was rapidly activated in rifampicin-treated mice. Hepatic PPARγ, a downstream target of PXR, was transcriptionally up-regulated. Taken together, the increased hepatic lipid synthesis and uptake of fatty acids from circulation into liver jointly contribute to rifampicin-induced hepatic lipid accumulation. The increased uptake of fatty acids from circulation into liver might be partially attributed to rifampicin-induced up-regulation of PPARγ and its target genes.

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“…Fatty acid metabolism was reported to be in uenced by Vitamin D de ciency and consequently increased the risk of tuberculosis infection [31]. N-Acetylgalactosamine, a substrate of arylsulfatase B (N-acetylgalactosamine-4-sulfatase), was proved to contribute to intracellular oxygen signaling and in uence hypoxia [32], mannitol, an inhibitor of CYP2E1 [33], could improve lung function in cystic brosis [34], Deoxyuridine troposphere nucleotidohydrolase, using deoxyuridine as a substrate, is a drug target against mycobacterium infections [35], Carnosine is an endogenous antioxidant widely distributed in excitable tissues[36], owning cytoprotective properties in primary cultured rat hepatocytes [37], Methylguanidine could inhibit lymphocyte transformation in vitro [38]. The concordance between the ndings in previous reports and the present study suggested that the M. marinum challenged zebra sh is a suitable model in mimicking tuberculosis infection in human.…”

Section: Discussionmentioning

confidence: 99%

Calcitriol Exerts Prophylactic Anti-Mycobacterium Effect In A Dose-Dependent Manner

Gao

et al. 2021

Preprint

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Vitamin D was empirically applied for Tuberculosis (TB) treatment in the past, and is currently used as an adjuvant for TB therapy. Although an increasing pile of evidences suggests that vitamin D has no therapeutic effect against TB infection, the prophylactic effect of vitamin D in preventing TB remains largely undetermined. To experimentally valuate the potential prophylactic effect of calcitriol (the active form of vitamin D) against mycobacterium infection, we performed dose-gradient calcitriol soaking in 30-day-old zebrafish before Mycobacterium marinum (M. marinum) challenge through tail vein injection. 1H-NMR metabolomics analysis was further performed for illustration of potential mechanisms underlying the prophylactic effect of calcitriol against M. marinum. The results suggested that calcitriol exerts dose-dependent prophylactic anti-mycobacterium effects, i.e., the bacterial load and the corresponding inflammatory factors (IL-1β, TNF-α, and IFN-γ) expressions in M. marinum challenged zebrafish were reduced by low-dose (25 µg/L) or high-dose (2500 µg/L) calcitriol soaking, rather than by moderate-dose (250 µg/L) calcitriol soaking. Body weight of the M. marinum challenged zebrafish was recovered by high-dose prophylactic calcitriol soaking rather than by low-dose or moderate-dose calcitriol. The 1H-NMR metabolomic profiling identified 29 metabolites with altered abundance among the dose-gradient calcitriol groups, among which 22 metabolites were co-varied with the dose of calcitriol, the rest 7 metabolites were co-varied with the bacterial load and the inflammatory response in term of cytokine expression. Further pathway analysis indicated that the glycine, serine, and threonine metabolism pathway was the activated in both of the two metabolite groups, indicating that the pathway was altered by dose-gradient of calcitriol and was in response to M. marinum infection in zebrafish. The results of the present study suggested that the activation of glycine, serine and threonine metabolism pathway may play a potential role for the dose-dependent anti-mycobacterium effect induced by prophylactic calcitriol soaking.

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Selected Pharmaceutical Excipient Prevent Isoniazid and Rifampicin Induced Hepatotoxicity

Abstract: Mannitol, an FDA-approved excipient, was found to be a CYP2E1 inhibitor. Mannitol may be a useful adjuvant for drugs that induce hepatotoxicity through CYP2E1, such as INH and RIF.

Cited by 12 publications

References 36 publications

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

Rifampicin-Induced Hepatic Lipid Accumulation: Association with Up-Regulation of Peroxisome Proliferator-Activated Receptor γ in Mouse Liver

Calcitriol Exerts Prophylactic Anti-Mycobacterium Effect In A Dose-Dependent Manner

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