Protective Effects of Kaempferol on Isoniazid- and Rifampicin-Induced Hepatotoxicity

Shih, Tiffany Ting-Fang; Young, Ton-Ho; Lee, Herng Sheng; Hsieh, Chih-Ming; Hu, Oliver Yoa Pu

doi:10.1208/s12248-013-9490-6

Cited by 60 publications

(37 citation statements)

References 35 publications

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“…Three cytochrome P450s enzymes, CYP2E1, CYP1A2 and CYP3A4, play a major role in ethanol metabolism in the liver (11,12), and CYP1A2 is also involved in the metabolism of kaempferol, as confirmed in a previous in vitro study (13). As a potent inhibitor of CYP2E1 and CYP 3A4, kaempferol can inhibit ethanol metabolism (14,15). In our investigations, kaempferol and ethanol co-administration clearly increased the AUC (Fig.…”

Section: Resultssupporting

confidence: 87%

Pharmacokinetic evaluation of the interaction between oral kaempferol and ethanol in rats

et al. 2016

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This study was aimed at investigating the effect of ethanol on oral bioavailability of kaempferol in rats, namely, at disclosing their possible interaction. Kaempferol (100 or 250 mg kg-1 bm) was administered to the rats by oral gavage with or without ethanol (600 mg kg-1 bm) co-administration. Intravenous administration (10 and 25 mg kg-1 bm) of kaempferol was used to determine the bioavailability. The concentration of kaempferol in plasma was estimated by ultra high performance liquid chromatography. During coadministration, a significant increase of the area under the plasma concentration-time curve as well as the peak concentration were observed, along with a dramatic decrease in total body clearance. Consequently, the bioavailability of kaempferol in oral control groups was 3.1 % (100 mg kg-1 bm) and 2.1 % (250 mg kg-1 bm). The first was increased by 4.3 % and the other by 2.8 % during ethanol co-administration. Increased permeability of cell membrane and ethanolkaempferol interactions on CYP450 enzymes may enhance the oral bioavailability of kaempferol in rats.

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Section: Resultssupporting

confidence: 87%

Pharmacokinetic evaluation of the interaction between oral kaempferol and ethanol in rats

et al. 2016

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“…However, in rats or mice, even INH/rifampicin cotreatment did not model the toxicity seen in humans. Rather, the cotreatment mildly increased the leakage of liver enzymes and caused vacuolization of centrilobular hepatocytes, and increased the number of apoptotic cells in the liver, without causing overt liver damage . Only when using human hepatocytes in culture, rifampicin potentiated INH toxicity .…”

Section: Mechanisms Underlying Inh‐induced Liver Injurymentioning

confidence: 97%

Mechanisms of isoniazid‐induced idiosyncratic liver injury: Emerging role of mitochondrial stress

Boelsterli

Lee

2014

J of Gastro and Hepatol

117

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Idiosyncratic drug-induced liver injury (DILI) is a significant adverse effect of antitubercular therapy with isoniazid (INH). Although the drug has been used for many decades, the underlying mode of action (both patient-specific and drug-specific mechanisms) leading to DILI are poorly understood. Among the patient-specific determinants of susceptibility to INH-associated DILI, the importance of HLA genetic variants has been increasingly recognized, whereas the role of polymorphisms of drug-metabolizing enzymes (NAT2 and CYP2E1) has become less important and remains controversial. However, these polymorphisms are merely correlative, and other molecular determinants of susceptibility have remained largely unknown. Regarding the drug-specific mechanisms underlying INHinduced liver injury, novel concepts have been emerging. Among these are covalent protein adduct formation via novel reactive intermediates, leading to hapten formation and a potential immune response, and interference with endogenous metabolism. Furthermore, INH and/or INH metabolites (e.g. hydrazine) can cause mitochondrial injury, which can lead to mitochondrial oxidant stress and impairment of energy homeostasis. Recent studies have revealed that underlying impairment of complex I function can trigger massive hepatocellular injury induced by otherwise nontoxic concentrations of INH superimposed on these mitochondrial deficiencies. This review discusses these emerging new paradigms of INH-induced DILI and highlights recent insights into the mechanisms, as well as points to the existing large gaps in our understanding of the pathogenesis.

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“…CYP2E1 inhibitors have proven to have a protective effect during co-treatment with isoniazid and rifampicin [59]. Mice treated with a CYP2E1 inhibitor, kaempferol, before co-treatment with isoniazid and rifampicin have a milder liver injury upon histological examination, such as hepatocellular disintegration and vacillation.…”

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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Protective Effects of Kaempferol on Isoniazid- and Rifampicin-Induced Hepatotoxicity

Cited by 60 publications

References 35 publications

Pharmacokinetic evaluation of the interaction between oral kaempferol and ethanol in rats

Pharmacokinetic evaluation of the interaction between oral kaempferol and ethanol in rats

Mechanisms of isoniazid‐induced idiosyncratic liver injury: Emerging role of mitochondrial stress

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

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