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Protective effects of kaempferol on isoniazid- and rifampicin-induced hepatotoxicity.

ABSTRACT: Isoniazid (INH) and rifampicin (RIF) are the first-line drugs for antituberculosis (anti-TB) chemotherapy. The levels of serum transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] are abnormal in 27% of patients undergoing INH and RIF treatments and in 19% of patients undergoing treatment with INH alone. Cytochrome P450 2E1 (CYP2E1) metabolizes many toxic substrates, including ethanol, carbon tetrachloride, and INH, which ultimately results in liver injury. The objective of this study was to screen for CYP2E1 inhibitors in vitro and investigate whether the selected compound could prevent INH/RIF-induced hepatotoxicity in vivo. We screened 83 known compounds from food and herbal medicines as inhibitors of CYP2E1. The hepatotoxic dose of INH/RIF was 50/100 mg kg(-1) day(-1). Hepatotoxicity was assessed using galactose single-point (GSP) method (a quantitative measurement of liver function), histopathological examination of the liver, malondialdehyde (MDA) assay, and measurement of AST and ALT activities. Kaempferol inhibited CYP2E1 activity in mice by 0.31- to 0.48-fold (p?

SUBMITTER: Shih TY

PROVIDER: S-EPMC3691431 | biostudies-other | 2013 Jul

REPOSITORIES: biostudies-other

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Protective effects of kaempferol on isoniazid- and rifampicin-induced hepatotoxicity.

Shih Tung-Yuan TY Young Ton-Ho TH Lee Herng-Sheng HS Hsieh Chung-Bao CB Hu Oliver Yoa-Pu OY

The AAPS journal 20130417 3

Isoniazid (INH) and rifampicin (RIF) are the first-line drugs for antituberculosis (anti-TB) chemotherapy. The levels of serum transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] are abnormal in 27% of patients undergoing INH and RIF treatments and in 19% of patients undergoing treatment with INH alone. Cytochrome P450 2E1 (CYP2E1) metabolizes many toxic substrates, including ethanol, carbon tetrachloride, and INH, which ultimately results in liver injury. The obj ...[more]

PMID: 23591749

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Project description:In recent years, it has been increasingly suggested that the consumption of natural polyphenols, in moderate amounts, is beneficial for health. The aim of this study was to investigate the efficacy of a red wine (the administered dose of 7 mL/kg/day being equivalent to ~16.5 mg/kg/day total polyphenols) compared to a white wine (the administered dose of 7 mL/kg/day being equivalent to ~1.7 mg/kg/day total polyphenols), on the prevention of acrylamide-induced subacute hepatic injury and oxidative stress in Wistar rats. Hepatic damage due to acrylamide intoxication (the administered dose being 250 µg/kg body weight, for 28 days, by intragastric gavage) was assessed by employing biochemical parameters (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) and by histopathological studies. Markers of oxidative damage were measured in terms of plasma malondialdehyde (MDA), hepatic Thiobarbituric Acid Reactive Substances (TBARS) and glutathione (GSH) levels, and liver antioxidant enzyme (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)) activities. Regarding hepatic enzyme activities, treatment with red wine significantly decreased the AST values (p < 0.05), while for the ALT values only a normalization tendency was observed. Treatment with red wine and white wine, respectively, significantly prevented the increase in MDA and TBARS levels (p < 0.05), as well as the depletion of GSH (p < 0.05). Red wine treatment normalized the activities of the antioxidant enzymes CAT and SOD in rats intoxicated with acrylamide, while supplementing the diet with white wine did not produce significant differences in the antioxidant enzyme activities. Histopathological findings revealed a moderate protective effect of red wine after four weeks of daily consumption. Our findings provide evidence that red wine, having a higher phenolic content than white wine, has a significant protective effect on oxidative stress and liver injury induced by acrylamide in rats, through its antioxidative activity.

Project description:Isoniazid (INH) is a first-line antituberculosis drug. The incidence of adverse reactions accompanied by inflammation in the liver during drug administration to tuberculosis patients is high and severely affects clinical treatment. To better understand the mechanism of hepatotoxicity induced by INH under the inflammatory state, we compared the differences in levels of hepatotoxicity from INH between normal zebrafish and zebrafish in an inflammatory state to elucidate the hepatotoxic mechanism using different endpoints such as mortality, malformation, inflammatory effects, liver morphology, histological changes, transaminase analysis, and expression levels of certain genes. The results showed that the toxic effect of INH in zebrafish in an inflammatory state was more obvious than that in normal zebrafish, that liver size was significantly decreased as measured by liver fatty acid binding protein (LFABP) reporter fluorescence and intensity, and that alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly increased. Hematoxylin and eosin (HE) staining and electron microscopy showed that hepatocyte injury was more obvious in the inflammatory state. In the inflammatory state, INH significantly increased the expression levels of endoplasmic reticulum stress (ERS)-related factors (GRP78, ATF6, PERK, IRE1, XBP1s, GRP94, and CHOP), autophagy-related factors (beclin 1, LC3, Atg3, and Atg12), and apoptosis-related factors (caspase-3, caspase-8, caspase-9, Bax, p53, and Cyt) in larvae. Correlational analyses indicated that the transcription levels of the inflammatory factors interleukin-1b (IL-1b), tumor necrosis factor beta (TNF-β), cyclooxygenase 2 (COX-2), and TNF-ɑ were strongly positively correlated with ALT and AST. Furthermore, the ERS inhibitor sodium 4-phenylbutyrate (4-PBA) could ameliorate the hepatotoxicity of INH-lipopolysaccharide (LPS) in zebrafish larvae. These results indicated that INH hepatotoxicity was enhanced in the inflammatory state. ERS and its mediated autophagy and apoptosis pathways might be involved in INH-induced liver injury promoted by inflammation.

Dataset Information

Protective effects of kaempferol on isoniazid- and rifampicin-induced hepatotoxicity.

Publications

Protective effects of kaempferol on isoniazid- and rifampicin-induced hepatotoxicity.

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