Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 18 de 18
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Pharmacol Res ; 155: 104752, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32169656

RESUMO

As a potential drug for treating inflammatory, autoimmune diseases and cancers, triptolide (TP) is greatly limited in clinical practice due to its severe toxicity, particularly for liver injury. Recently, metabolic homeostasis was vitally linked to drug-induced liver injury and gut microbiota was established to play an important role. In this study, we aimed to investigate the functions of gut microbiota on TP-induced hepatotoxicity using metabolomics in mice. Here, predepletion of gut microbiota by antibiotic treatment strikingly aggravated liver injury and caused mortality after treated with a relatively safe dosage of TP at 0.5 mg/kg, which could be reversed by gut microbial transplantation. The loss of gut microbiota prior to TP treatment dramatically elevated long chain fatty acids and bile acids in plasma and liver. Further study suggested that gut microbiota-derived propionate contributed to the protective effect of gut microbiota against TP evidenced by ameliorative inflammatory level (Tnfa, Il6 and Cox2), ATP, malondialdehyde and hepatic histology. Supplementing with propionate significantly decreased the mRNA levels of genes involved in fatty acid biosynthesis (Srebp1c, Fasn and Elovl6), resulting in the decreased long chain fatty acids in liver. Moreover, TP restricted the growth of Firmicutes and led to the deficiency of short chain fatty acids in cecum content. In conclusion, our study warns the risk for TP and its preparations when antibiotics are co-administrated. Intervening by foods, prebiotics and probiotics toward gut microbiota or supplementing with propionate may be a clinical strategy to improve toxicity induced by TP.

2.
Xenobiotica ; : 1-14, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32174209

RESUMO

Coumarins have aroused high interests due to their diverse bioactivities. Understanding of its metabolism contributes to determine the druggability of coumarin in vivo.A sensitive and efficient strategy based on ultra-performance liquid chromatography-mass spectrometer (UPLC-MS) analysis combined with various data-processing techniques including metabolomics and multiple mass defect filter (MMDF) was established for the comprehensive screening and elucidation of potential coumarin metabolites.Total 20 metabolites of scoparone were identified in this study, including 14 undescribed metabolites. The metabolism of two other similar coumarins scopoletin and esculetin also could be determined using this strategy.By the established strategy, this study gives the insights about the major metabolic pathways of scoparone in vivo and in vitro metabolism, including demethylation, hydroxylation, hydration, cysteine conjugation, glucuronide conjugation and sulfate conjugation. Additionally, the metabolic pathways of scopoletin and esculetin were determined as hydroxylation, glucuronidation and sulfation. These results contribute to the understanding of metabolic characterization of coumarins, and demonstrate that the combination of UPLC-MS-based metabolomics and MMDF is a powerful approach to determine the metabolic pathways of coumarin compounds.

3.
J Pharm Biomed Anal ; 180: 113045, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31887668

RESUMO

Nintedanib is a promising tyrosine kinase inhibitor for clinically treating idiopathic pulmonary fibrosis (IPF). Some clinical cases reported that nintedanib treatment can cause hepatotoxicity and myocardial toxicity. U. S. FDA warns the potential drug-drug interaction when it is co-administrated with other drugs. In order to understand the potential toxicity of nintedanib and avoid drug-drug interaction, the metabolism of nintedanib was systematically investigated in human liver microsomes and mice using metabolomics approach, and the toxicity of metabolites was predicted by ADMET lab. Nineteen metabolites were detected in vivo and in vitro metabolism, and 8 of them were undescribed. Calculated partition coefficients (Clog P) were used to distinguish the isomers of nintedanib metabolites in this study. The major metabolic pathways of nintedanib majorly included hydroxylation, demethylation, glucuronidation, and acetylation reactions. The ADMET prediction indicated that nintedanib was a substrate of the cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). And nintedanib and most of its metabolites might possess potential hepatotoxicity and cardiotoxicity. This study provided a global view of nintedanib metabolism, which could be used to understand the mechanism of adverse effects related to nintedanib and its potential drug-drug interaction.

4.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3562-3568, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602923

RESUMO

The mass spectrometry-based metabolomics method was used to systematically investigate the formation of celastrol metabolites,and the effect of celastrol on endogenous metabolites. The mice plasma,urine and feces samples were collected after oral administration of celastrol. Ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry( UPLC-QTOF-MS) was applied to analyze the exogenous metabolites of celastrol and its altered endogenous metabolites. Mass defect filtering was adopted to screen for the exogenous metabolites of celastrol. Multivariate statistical analysis was used to identify the endogenous metabolites affected by celastrol. Celastrol and its eight metabolites were detected in urine and feces of mice,and 5 metabolites of them were reported for the first time. The hydroxylated metabolites were observed in the metabolism of both human liver microsomes and mouse liver microsomes. Further recombinant enzyme experiments revealed CYP3 A4 was the major metabolic enzyme involved in the formation of hydroxylated metabolites. Urinary metabolomics revealed that celastrol can affect the excretion of intestinal bacteria-related endogenous metabolites,including hippuric acid,phenylacetylglycine,5-hydroxyindoleacetic acid,urocanic acid,cinnamoylglycine,phenylproplonylglycine and xanthurenic acid. These results are helpful to elucidate the metabolism and disposition of celastrol in vivo,and its mechanism of action.


Assuntos
Metabolômica , Triterpenos/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Humanos , Espectrometria de Massas , Camundongos , Microssomos Hepáticos/metabolismo , Triterpenos/metabolismo
5.
Chem Res Toxicol ; 32(10): 1965-1976, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31468958

RESUMO

Elemicin is a constituent of natural aromatic phenylpropanoids present in many herbs and spices. However, its potential to cause toxicity remains unclear. To examine the potential toxicity and associated mechanism, elemicin was administered to mice for 3 weeks and serum metabolites were examined. Enlarged livers were observed in elemicin-treated mice, which were accompanied by lower ratios of unsaturated- and saturated-lysophosphatidylcholines in plasma, and inhibition of stearoyl-CoA desaturase 1 (Scd1) mRNA expression in liver. Administration of the unsaturated fatty acid oleic acid reduced the toxicity of 1'-hydroxylelemicin, the primary oxidative metabolite of elemicin, while treatment with the SCD1 inhibitor A939572 potentiated its toxicity. Furthermore, the in vitro use of recombinant human CYPs and chemical inhibition of CYPs in human liver microsomes revealed that CYP1A1 and CYP1A2 were the primary CYPs responsible for elemicin bioactivation. Notably, the CYP1A2 inhibitor α-naphthoflavone could attenuate the susceptibility of mice to elemicin-induced hepatomegaly. This study revealed that metabolic activation of elemicin leads to SCD1 inhibition in liver, suggesting that upregulation of SCD1 may serve as potential intervention strategy for elemicin-induced toxicity.

6.
J Agric Food Chem ; 67(29): 8243-8252, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31271289

RESUMO

Elemicin, an alkenylbenzene constituent of natural oils of several plant species, is widely distributed in food, dietary supplements, and medicinal plants. 1'-Hydroxylation is known to cause metabolic activation of alkenylbenzenes leading to their potential toxicity. The aim of this study was to explore the relationship between elemicin metabolism and its toxicity through comparing the metabolic maps between elemicin and 1'-hydroxyelemicin. Elemicin was transformed into a reactive metabolite of 1'-hydroxyelemicin, which was subsequently conjugated with cysteine (Cys) and N-acetylcysteine (NAC). Administration of NAC could significantly ameliorate the elemicin- and 1'-hydroxyelemicin-induced cytotoxicity of HepG2 cells, while depletion of Cys with diethyl maleate (DEM) increased cytotoxicity. Recombinant human CYP screening and CYP inhibition experiments revealed that multiple CYPs, notably CYP1A1, CYP1A2, and CYP3A4, were responsible for the metabolic activation of elemicin. This study revealed that metabolic activation plays a critical role in elemicin cytotoxicity.


Assuntos
Pirogalol/análogos & derivados , Ativação Metabólica , Biotransformação , Sobrevivência Celular/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Células Hep G2 , Humanos , Hidroxilação , Estrutura Molecular , Pirogalol/química , Pirogalol/metabolismo , Pirogalol/toxicidade
7.
Toxicol Sci ; 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31241159

RESUMO

Triptolide (TP), one of the main active ingredients in Tripterygium wilfordii Hook F, is clinically used to treat immune diseases but is known to cause liver injury. The aim of this study was to investigate the biomarkers for TP-induced hepatotoxicity in mice and to determine potential mechanisms of its liver injury. LC/MS-based metabolomics was used to determine the metabolites that were changed in TP-induced liver injury. The accumulation of long-chain acylcarnitines in serum indicated that TP exposure disrupted endogenous peroxisome proliferator-activated receptor α (PPARα) signaling. TP-induced liver injury could be alleviated by treatment of mice with the PPARα agonist fenofibrate, while the PPARα antagonist GW6471 increased hepatotoxicity. Furthermore, fenofibrate did not protect Ppara-/- mice from TP-induced liver injury, suggesting an essential role for the PPARα in the protective effect of fenofibrate. Elevated long-chain acylcarnitines may protect TP-induced liver injury through activation of the NOTCH-NRF2 pathway as revealed in primary mouse hepatocytes and in vivo. In agreement with these observations in mice, the increase of long-chain acylcarnitines was observed in the serum of patients with cholestatic liver injury compared to heathy volunteers. These data demonstrated the role of PPARα and long-chain acylcarnitines in TP-induced hepatotoxicity, and suggest that modulation of PPARα may protect against drug-induced liver injury.

8.
Br J Pharmacol ; 176(13): 2162-2178, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30875096

RESUMO

BACKGROUND AND PURPOSE: Sunitinib is a small-molecule TK inhibitor associated with hepatotoxicity. The mechanisms of its toxicity are still unclear. EXPERIMENTAL APPROACH: In the present study, mice were treated with 60, 150, and 450 mg·kg-1 sunitinib to evaluate sunitinib hepatotoxicity. Sunitinib metabolites and endogenous metabolites in liver, serum, faeces, and urine were analysed using ultra-performance LC electrospray ionization quadrupole time-of-flight MS-based metabolomics. KEY RESULTS: Four reactive metabolites and impaired clearance of sunitinib in liver played a dominant role in sunitinib-induced hepatotoxicity. Using a non-targeted metabolomics approach, various metabolic pathways, including mitochondrial fatty acid ß-oxidation (ß-FAO), bile acids, lipids, amino acids, nucleotides, and tricarboxylic acid cycle intermediates, were disrupted after sunitinib treatment. CONCLUSIONS AND IMPLICATIONS: These studies identified significant alterations in mitochondrial ß-FAO and bile acid homeostasis. Activation of PPARα and inhibition of xenobiotic metabolism may be of value in attenuating sunitinib hepatotoxicity.

9.
J Agric Food Chem ; 67(15): 4328-4336, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30912427

RESUMO

Myristicin is widely distributed in spices and medicinal plants. The aim of this study was to explore the role of metabolic activation of myristicin in its potential toxicity through a metabolomic approach. The myristicin- N-acetylcysteine adduct was identified by comparing the metabolic maps of myristicin and 1'-hydroxymyristicin. The supplement of N-acetylcysteine could protect against the cytotoxicity of myristicin and 1'-hydroxymyristicin in primary mouse hepatocytes. When the depletion of intracellular N-acetylcysteine was pretreated with diethyl maleate in hepatocytes, the cytotoxicity induced by myristicin and 1'-hydroxymyristicin was deteriorated. It suggested that the N-acetylcysteine adduct resulting from myristicin bioactivation was closely associated with myristicin toxicity. Screening of human recombinant cytochrome P450s (CYPs) and treatment with CYP inhibitors revealed that CYP1A1 was mainly involved in the formation of 1'-hydroxymyristicin. Collectively, this study provided a global view of myristicin metabolism and identified the N-acetylcysteine adduct resulting from myristicin bioactivation, which could be used for understanding the mechanism of myristicin toxicity.


Assuntos
Compostos de Benzil/metabolismo , Compostos de Benzil/toxicidade , Dioxolanos/metabolismo , Dioxolanos/toxicidade , Hepatócitos/efeitos dos fármacos , Pirogalol/análogos & derivados , Acetilcisteína/química , Acetilcisteína/metabolismo , Ativação Metabólica , Animais , Compostos de Benzil/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocromo P-450 CYP1A1/metabolismo , Dioxolanos/química , Hepatócitos/citologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pirogalol/química , Pirogalol/metabolismo , Pirogalol/toxicidade
10.
Mol Cell Proteomics ; 18(3): 520-533, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30617157

RESUMO

Celastrol, derived from the roots of the Tripterygium Wilfordi, shows a striking effect on obesity. In the present study, the role of celastrol in cholestasis was investigated using metabolomics and transcriptomics. Celastrol treatment significantly alleviated cholestatic liver injury in mice induced by α-naphthyl isothiocyanate (ANIT) and thioacetamide (TAA). Celastrol was found to activate sirtuin 1 (SIRT1), increase farnesoid X receptor (FXR) signaling and inhibit nuclear factor-kappa B and P53 signaling. The protective role of celastrol in cholestatic liver injury was diminished in mice on co-administration of SIRT1 inhibitors. Further, the effects of celastrol on cholestatic liver injury were dramatically decreased in Fxr-null mice, suggesting that the SIRT1-FXR signaling pathway mediates the protective effects of celastrol. These observations demonstrated a novel role for celastrol in protecting against cholestatic liver injury through modulation of the SIRT1 and FXR.


Assuntos
Colestase Intra-Hepática/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/metabolismo , Sirtuína 1/metabolismo , Triterpenos/administração & dosagem , 1-Naftilisotiocianato/efeitos adversos , Adulto , Animais , Colestase Intra-Hepática/sangue , Colestase Intra-Hepática/induzido quimicamente , Colestase Intra-Hepática/genética , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Metabolômica/métodos , Camundongos , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Tioacetamida/efeitos adversos , Resultado do Tratamento , Triterpenos/farmacologia
11.
Xenobiotica ; 49(6): 655-670, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29897827

RESUMO

To elucidate the metabolism of pazopanib, a metabolomics approach was performed based on ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry. A total of 22 pazopanib metabolites were identified in vitro and in vivo. Among these metabolites, 17 were novel, including several cysteine adducts and aldehyde derivatives. By screening using recombinant CYPs, CYP3A4 and CYP1A2 were found to be the main forms involved in the pazopanib hydroxylation. Formation of a cysteine conjugate (M3), an aldehyde derivative (M15) and two N-oxide metabolites (M18 and M20) from pazopanib could induce the oxidative stress that may be responsible in part for pazopanib-induced hepatotoxicity. Morphological observation of the liver suggested that pazopanib (300 mg/kg) could cause liver injury. The aspartate transaminase and alanine aminotransferase in serum significantly increased after pazopanib (150, 300 mg/kg) treatment; this liver injury could be partially reversed by the broad-spectrum CYP inhibitor 1-aminobenzotriazole (ABT). Metabolomics analysis revealed that pazopanib could significantly change the levels of L-carnitine, proline and lysophosphatidylcholine 18:1 in liver. Additionally, drug metabolism-related gene expression analysis revealed that hepatic Cyp2d22 and Abcb1a (P-gp) mRNAs were significantly lowered by pazopanib treatment. In conclusion, this study provides a global view of pazopanib metabolism and clues to its influence on hepatic function.


Assuntos
Antineoplásicos/toxicidade , Fígado/efeitos dos fármacos , Pirimidinas/toxicidade , Sulfonamidas/toxicidade , Alanina Transaminase/sangue , Animais , Antineoplásicos/metabolismo , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Cromatografia Líquida de Alta Pressão , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/fisiologia , Fígado/metabolismo , Fígado/patologia , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Análise Multivariada , Estresse Oxidativo/efeitos dos fármacos , Pirimidinas/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Sulfonamidas/metabolismo
12.
Phytochemistry ; 156: 167-175, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30312932

RESUMO

Tripterygium hypoglaucum (H. Lév.) Hutch. has been used to remedy rheumatoid arthritis, however, it shows frequent toxicity to the body. In this study, liquid chromatograph-mass spectrometer (LC-MS) was guided to characterize abietanes diterpenoids with anti-inflammatory activity from the stem of T. hypoglaucum. Thirteen undescribed abietanes diterpenoids were isolated and purified, and their chemical structure was identified using various spectroscopic methods. These compounds belonged to abietanes with splitting C ring, abietanes with benzenoid rings, diterpene quinoids, diterpene quinoids with lactone rings, and abietanes with benzenoid and lactone rings, respectively. Lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages was used to evaluate anti-inflammatory activity of the compounds. The results indicated that hypoglicin B-G and hypoglicin J-M exhibited inhibitory activity of NO production with the IC50 values of 6.01, 25.21, 8.29, 3.63, 0.72, 0.89, 36.91, 0.82, 2.85, 11.92 µM, respectively. Among these compounds, compound hypoglicin L showed high anti-inflammatory activity and low toxicity (SI = 5.02 × 104). Further QPCR analysis revealed that hypoglicin D and hypoglicin L can inhibit the mRNA expression of iNOS in LPS-stimulated RAW264.7 cells at doses of 12.5 and 3.13 µM, respectively. Taken together, ten anti-inflammatory diterpenoids were found from T. hypoglaucum in this study.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diterpenos/farmacologia , Óxido Nítrico/antagonistas & inibidores , Tripterygium/química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Conformação Molecular , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade
13.
Biomed Chromatogr ; 32(12): e4359, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30091800

RESUMO

Drug-induced liver injury is a clinically leading side-effect of drugs. In the present study, a liquid chromatography mass spectrometry-based metabolomics protocol was optimized for extraction and analysis of endogenous metabolites from liver tissue during hepatotoxicity. Various extraction solutions, resuspension solutions, extraction folds and dissolution methods for the supernatant were compared using the number of extracted total ions, relative response and relative extraction efficiency of targeted metabolites from liver tissue. The polar and nonpolar endogenous metabolites associated with liver injury were analyzed by hydrophilic interaction chromatography and reversed-phase liquid chromatography with UPLC-QTOFMS. The results indicated that extraction with 10-fold 50% acetonitrile in water and the supernatant diluted (1:1) with 100% acetonitrile rather than resuspension was the optimal extraction protocol. Subsequently, the optimized method was able to examine the change in metabolites in mouse liver tissue resulting from treatment with a toxic natural product, toosendanin. Taken together, the optimized extraction and analytical protocol provides high reliability and reproducibility for polar and nonpolar metabolites in liver tissue and may be suitable for metabolomics analysis of liver injury induced by drugs or chemicals.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Fígado/química , Espectrometria de Massas/métodos , Metaboloma/efeitos dos fármacos , Metabolômica/métodos , Animais , Cromatografia Líquida/métodos , Medicamentos de Ervas Chinesas/toxicidade , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Testes de Toxicidade
14.
Food Chem Toxicol ; 120: 253-260, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30009888

RESUMO

Cholestasis is characterized by the obstruction of bile duct, including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The complicated etiology and injury mechanism greatly limits the development of new drugs for its treatment. To better understand the mechanism of cholestatic liver damage, ultra-performance liquid chromatography-linked electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) and multivariate data analysis were used to determine the metabolic changes in three recognized mouse cholestasis models. The cholestatic liver damage was generated by alphanaphthyl isothiocyanate (ANIT), 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and lithocholic acid (LCA). The results indicated that the levels of bile acids were commonly increased in plasma of three mouse cholestasis models, while arginine was decreased. The level of plasma glutathione was decreased in ANIT- and LCA-induced intrahepatic PBC and PSC, respectively. But, the liver glutathione was decreased in DDC induced extrahepatic PSC. The level of plasma phospholipids was elevated in ANIT and DDC models, whereas that was depleted in LCA model. And protoporphyrin IX was significantly increased in the liver of DDC model. These metabolomics data could potentially distinguish the metabolic differences of three types of cholestasis, contributing to the understanding of the potential mechanism of cholestatic liver damage.


Assuntos
Colangite Esclerosante/metabolismo , Colestase/metabolismo , Colestase/patologia , Cirrose Hepática Biliar/metabolismo , Metabolômica , Animais , Arginina/sangue , Ácidos e Sais Biliares/sangue , Biomarcadores/metabolismo , Colangite Esclerosante/sangue , Colangite Esclerosante/patologia , Cromatografia Líquida , Modelos Animais de Doenças , Glutationa/sangue , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/patologia , Masculino , Espectrometria de Massas , Camundongos Endogâmicos C57BL , Fosfolipídeos/sangue
15.
J Pharm Biomed Anal ; 159: 524-535, 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-30055476

RESUMO

Regorafenib is a novel tyrosine kinase inhibitor, which has been approved by the United States Food and Drug Administration for the treatment of various tumors. The purpose of the present study was to describe the metabolic map of regorafenib, and investigate its effect on liver function. Mass spectrometry-based metabolomics approach integrated with multiple mass defect filter was used to determine the metabolites of regorafenib in vitro incubation mixtures (human liver microsomes and mouse liver microsomes), serum, urine and feces samples from mice treated with 80 mg/kg regorafenib. Eleven metabolites including four novel metabolites were identified in the present investigation. As halogen substituted drug, reductive defluorination and oxidative dechlorination metabolites of regorafenib were firstly report in present study. By screening using recombinant cytochrome P450 s (CYPs), CYP3A4 was found to be the principal isoforms involved in regorafenib metabolism. The predication with a molecular docking model confirmed that regorafenib had potential to interact with the active sites of CYP3A4, CYP3A5 and CYP2D6. Serum chemistry analysis revealed no evidence of hepatic damage from regorafenib exposure. This study provided a global view of regorafenib metabolism and its potential side-effects.


Assuntos
Metabolômica , Compostos de Fenilureia/farmacocinética , Piridinas/farmacocinética , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/urina , Citocromo P-450 CYP3A/metabolismo , Fezes/química , Humanos , Fígado/efeitos dos fármacos , Espectrometria de Massas , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Compostos de Fenilureia/sangue , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/urina , Piridinas/sangue , Piridinas/farmacologia , Piridinas/urina
16.
J Proteome Res ; 17(5): 1887-1897, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29664296

RESUMO

Nutmeg is a Traditional Chinese Medicine used to treat gastrointestinal diseases. Some reports have indicated that nutmeg has hepatoprotective activity. In this study, a thioacetamide (TAA)-induced acute liver injury model in mice was used to explore the mechanism of the protective effects of nutmeg extract (NME), including its major bioactive component myrislignan. The results indicated that NME could effectively protect TAA-induced liver damage as assessed by recovery of increased serumtransaminases, decrease in hepatic oxidative stress, and lower hepatic inflammation. Metabolomics analysis further revealed that treatment with NME led to the recovery of a series of lipids including lysophosphatidylcholines that were decreased and a lowering of acylcarnitines that were increased in mouse plasma and liver after TAA exposure. Gene expression analysis demonstrated that the hepatoprotective effect of NME was achieved by modulation of the peroxisome proliferator-activated receptor alpha (PPARα) as well as the decrease in oxidative stress. NME could not protect from TAA-induced liver injury in Ppara-null mice, suggesting that its protective effect was dependent on PPARα. Myrislignan, a representative neolignan in nutmeg, showed potent protective activity against TAA-induced liver toxicity. These data demonstrate that nutmeg alleviates TAA-induced liver injury through the modulation of PPARα and that the lignan compounds in nutmeg such as myrislignan partly contributed to this action.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Myristica , PPAR alfa/fisiologia , Animais , Carnitina/análogos & derivados , Carnitina/análise , Lipídeos/análise , Metabolômica , Camundongos , Camundongos Knockout , Estresse Oxidativo , Substâncias Protetoras/farmacologia , Tioacetamida/efeitos adversos
18.
Yao Xue Xue Bao ; 51(9): 1451-7, 2016 09.
Artigo em Chinês | MEDLINE | ID: mdl-29924542

RESUMO

An ultra performance liquid chromatography tandem quadrupole time-of-flight mass spectrometric method was developed for rapid analysis of glycerophospholipids in RAW264.7 macrophage. The modified Bligh-Dyer was applied to extract glycerophospholipids from RAW264.7 macrophage. The target compounds, detected by mass spectrometry in ESI(+) and ESI(-) mode, were separated by gradient elution with mobile phase (A) water(containing 10 mmol·L(-1) ammonium acetate and 0.25% acetic acid) and (B) acetonitrile/isopropanol (1 : 1) (containing 10 mmol·L(-1) ammonium acetate and 0.25% acetic acid). A total of 82 glycerophospholipids including 57 phosphatidylcholines (PCs), 21 phosphatidylethanolamines (PEs), three phosphatidylglycerols (PGs) and one phosphatidylinositol (PI) were deduced. The UHPLC-QTOF/MS method is rapid, simple and credible for targeting analysis of glycerophospholipids of RAW264.7 macrophage.


Assuntos
Glicerofosfolipídeos/análise , Macrófagos/química , Animais , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , Camundongos , Fosfatidilcolinas , Fosfatidiletanolaminas , Fosfatidilgliceróis , Fosfatidilinositóis , Células RAW 264.7
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA