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1.
Toxicol Lett ; 319: 148-154, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31707106

RESUMO

In vitro cytochrome P450 inhibition of major kratom alkaloids: mitragynine (MTG), speciogynine (SPG), speciocilliatine (SPC), corynantheidine (COR), 7-hydroxymitragynine (7HMG) and paynantheine (PAY) was evaluated using human liver microsomes (HLMs) to understand their drug-drug interaction potential. CYP450 isoform-specific substrates of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4/5 were incubated in HLMs with or without alkaloids. Preliminary CYP450 inhibition (IC50) data were generated for each of these isoforms. In addition, the type of inhibition and estimation of the inhibition constants (Ki) of MTG and COR were determined. Among the tested alkaloids, MTG and COR were potent inhibitors of CYP2D6 (IC50, 2.2 and 4.2 µM, respectively). Both MTG and COR exhibited competitive inhibition of CYP2D6 activity and the Ki were found to be 1.1 and 2.8 µM, respectively. SPG and PAY showed moderate inhibition of CYP2D6 activity. Additionally, moderate inhibitory effects by SPC, MTG, and SPG were observed on CYP2C19 activity. Interestingly, inhibition of only midazolam hydroxylase CYP3A4/5 activity by COR, PAY, and MTG was observed while no inhibitory effect was observed when testosterone was used as a probe substrate. In conclusion, MTG and COR may lead to clinically significant adverse drug interactions upon coadministration of drugs that are substantially metabolized by CYP2D6.


Assuntos
Alcaloides/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Interações de Medicamentos , Mitragyna/química , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Isoenzimas/efeitos dos fármacos , Isoenzimas/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo
2.
Chemosphere ; 238: 124538, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31454745

RESUMO

Although banned, dyes, such as Victoria pure blue BO (VPBO), are illicitly used in aquaculture to treat or prevent infections due to their therapeutic activities. The present study examined the formation of phase I and phase II metabolites derived from VPBO using trout liver microsomes and S9 proteins. The well-known malachite green (MG) dye was also studied as a positive control and to compare its metabolism with that of VPBO. First, we optimised the incubation conditions for the detection of VPBO and MG metabolites by studying the formation of cytochrome P450 (CYP) substrates. Using the determined conditions (2 h at 20 °C), we incubated VPBO with trout microsomal and S9 fractions induced with ß-naphtoflavone, and analysed the supernatant in a LC-LTQ-Orbitrap-HRMS system. The in vitro assays led to the detection of 16 VPBO metabolites from Phase I reactions, arising in particular from reactions with CYP1A. No metabolites were detected from Phase II reactions. The main metabolite detected, deethyl-VPBO, was CID-fragmented to determine its chemical structure, and thus recommend a potential biomarker for the control of VPBO in farmed fish foodstuffs.


Assuntos
Corantes/metabolismo , Peixes/metabolismo , Contaminação de Alimentos/análise , Compostos de Amônio Quaternário/metabolismo , Alimentos Marinhos , Animais , Aquicultura , Sistema Enzimático do Citocromo P-450/metabolismo , Metabolômica , Microssomos Hepáticos/metabolismo
3.
Zhongguo Zhong Yao Za Zhi ; 44(18): 4043-4047, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31872743

RESUMO

The purpose of this study was to investigate the effect of apigenin on UGT1 A1 enzyme activity and to predict the potential drug-drug interaction of apigenin in clinical use. First,on the basis of previous experiments,the binding targets and binding strength of apigenin to UGT1 A1 enzyme were predicted by computer molecular docking method. Then the inhibitory effect of apigenin on UGT1 A1 enzyme was evaluated by in vitro human liver microsomal incubation system. Molecular docking results showed that apigenin was docked into the active region of UGT1 A1 enzyme protein F,consistent with the active region of bilirubin docking,with moderate affinity. Apigenin flavone mother nucleus mainly interacted with amino acid residues ILE343 and VAL345 to form hydrophobic binding Pi-Alkyl. At the same time,the hydroxyl group on the mother nucleus and the amino acid residue LYS346 formed an additional hydrogen bond,which increased the binding of the molecule to the protein. These results suggested that the flavonoid mother nucleus structure had a special structure binding to the enzyme protein UGT1 A1,and the introduction of hydroxyl groups into the mother nucleus can increase the binding ability. In vitro inhibition experiments showed that apigenin had a moderate inhibitory effect on UGT1 A1 enzyme in a way of competitive inhibition,which was consistent with the results of molecular docking. The results of two experiments showed that apigenin was the substrate of UGT1 A1 enzyme,which could inhibit the activity of UGT1 A1 enzyme competitively,and there was a risk of drug interaction between apigenin and UGT1 A1 enzyme substrate in clinical use.


Assuntos
Apigenina/química , Bilirrubina/química , Interações de Medicamentos , Microssomos Hepáticos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Glucuronosiltransferase/metabolismo , Humanos , Ligações de Hidrogênio
4.
Zhongguo Zhong Yao Za Zhi ; 44(20): 4529-4537, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31872642

RESUMO

Ultra-fast performance liquid chromatography-mass spectrometry( UFLC-MS/MS) was used to study the anti-inflammatory active ingredient of Millettia pachyloba,6-methoxy-8,8-dimethyl-3-( 2,4,5-trimethoxyphenyl)-4 H,8 H-pyrano[2,3-f]chromen-4-one( HN-1),in liver microsomes of rats,mice,rhesus monkeys,Beagle dogs and humans metabolic stability,and compare the metabolic differences between different species. The metabolic phenotype in human liver microsomes was determined by chemical inhibitor method. Using UPLC-Q-TOF-MS/MS detection method,the in vitro metabolites of various liver microsomes were preliminarily inferred by comparing the samples incubated for 0 min and 60 min in vitro. The metabolites of HN-1 in SD rats were presumed by comparing feces,urine,plasma blanks and samples after administration. The results showed that the metabolism of HN-1 in various liver microsomes was stable,and the metabolic properties of dog and human liver microsomes were the closest. It is mainly catabolized by CYP1 A1,CYP2 D6 and CYP3 A4 isoenzymes in human liver microsomes. The metabolites of HN-1 in vitro and in vivo,including 3 in vitro metabolites and5 in vivo metabolites,were preliminarily estimated. The results laid the foundation for further pharmacological studies of HN-1.


Assuntos
Medicamentos de Ervas Chinesas , Millettia , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida de Alta Pressão , Cães , Humanos , Camundongos , Microssomos Hepáticos , Ratos , Ratos Sprague-Dawley
5.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1130-1131: 121829, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31670104

RESUMO

S011-2111 is a semicarbazone and chalcone hybrid demonstrating antiproliferative tumor cell-selective effects along with unique antimetastatic potential by mitigating PP2A-ß-catenin signalling pathway. The present study envisaged to explore the in vitro and in vivo pharmacokinetics of S011-2111. A sensitive and selective liquid chromatography-tandem mass spectrometry bioanalytical method was developed and validated to determine S011-2111. It has high permeability across intestinal membrane as observed in in situ single-pass intestinal perfusion study. It has high plasma protein binding and poor aqueous solubility. It was rapidly partitioning into plasma of blood, where it was moderately stable. In mice liver microsomal stability study, S011-2111 was stable against cytochrome P450 enzymes but undergoes rapid glucuronidation with intrinsic clearance of 148.6 ±â€¯48.3 µL/min/mg. Following 100 mg/kg oral dosing of S011-2111, the compound was detectable in the plasma samples up to 24 h with a maximum plasma concentration of 45 ±â€¯16.5 ng/mL at 2.4 ±â€¯0.1 h and absolute bioavailability of 1.68%. Knowledge from this research will assist in further development of S011-2111 as an anti-cancer agent.


Assuntos
Cromatografia Líquida/métodos , Inibidores Enzimáticos , Proteína Fosfatase 2/antagonistas & inibidores , Espectrometria de Massas em Tandem/métodos , beta Catenina/antagonistas & inibidores , Animais , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Eritrócitos , Feminino , Absorção Intestinal , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray/métodos
6.
Artigo em Inglês | MEDLINE | ID: mdl-31704446

RESUMO

Capsaicin (CAP) is a principal pungent ingredient in hot peppers, it is also employed as a common food additive, an efficient pharmaceutical component, or even a riot control agent. CAP exerts various pharmacological activities as well as associated adverse physiological responses and causes moderate toxicity if overused. A full screening and identification of CAP metabolites in combination with its main detoxification pathways are crucial for the clear demonstration on its pharmacological and toxicological significance. Here, we employed a post-acquisition data-mining metabolic screening approach to rapidly find and identify a broad range of CAP metabolites generated from in vitro human liver microsomes, based on an ultra-performance liquid chromatography-quadrupole orbitrap high resolution tandem mass spectrometric method. First, we collected full scan MS and MS/MS data sets by a data-dependent acquisition method in positive ion mode, and then we employed a modified mass defect filter and a diagnostic ion filter to screen and identify all the probable CAP metabolites, combining with information including retention time, accurate mass, characteristic fragments, and relevant drug biotransformation patterns. In comparison with the stable isotope-labeled CAP involved biotransformation products, we confirmed 19 functionalized metabolites and 13 glutathione (GSH) conjugates of CAP, in which 13 metabolites are reported for the first time. We then briefly depicted an overview metabolic pathway of CAP from the GSH detoxification viewpoint, revealed that various metabolites of CAP can be generated from single or multiple biotransformation and metabolic reactions. Both CAP and its reactive metabolites produced relevant GSH conjugates, which indicates a wide and important detoxification value of GSH conjugation way.


Assuntos
Capsaicina , Cromatografia Líquida/métodos , Glutationa/metabolismo , Microssomos Hepáticos/metabolismo , Espectrometria de Massas em Tandem/métodos , Biotransformação , Capsaicina/metabolismo , Capsaicina/farmacocinética , Humanos
7.
J Agric Food Chem ; 67(51): 14019-14026, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31725274

RESUMO

Flufiprole is an insecticide used in the rice field and may pose a potential threat to aquatic organisms including loach. To investigate the transformation products of flufiprole in loach, the accumulation, elimination, and tissue distribution in vivo as well as the metabolism in vitro at the enantiomeric level were studied. Flufiprole enantiomers rapidly accumulated and were metabolized to flufiprole sulfone, fipronil, and flufiprole amide in the tissues. Enantiomeric fractions showed the preferential accumulation and degradation of S-flufiprole. The residue of the chiral metabolite flufiprole amide was also enantioselective. The individual enantiomer treatment indicated that S-flufiprole was preferentially metabolized to flufiprole sulfone and R-flufiprole to fipronil. The metabolites were more persistent than flufiprole with longer half-lives. The metabolism in liver microsomes also reached consistent conclusions. The dietary risk assessment indicated that flufiprole would not cause unacceptable threats to human health. However, the metabolites of flufiprole should be considered in the risk evaluation.


Assuntos
Cipriniformes/metabolismo , Inseticidas/química , Inseticidas/metabolismo , Pirazóis/química , Pirazóis/metabolismo , Animais , Resíduos de Drogas/química , Resíduos de Drogas/metabolismo , Peixes/metabolismo , Contaminação de Alimentos/análise , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estereoisomerismo , Distribuição Tecidual , Poluentes Químicos da Água/química , Poluentes Químicos da Água/metabolismo
8.
Pharm Res ; 36(12): 170, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654151

RESUMO

PURPOSE: Many bioactive molecules show a type of solution phase behavior, termed promiscuous aggregation, whereby at micromolar concentrations, colloidal drug-rich aggregates are formed in aqueous solution. These aggregates are known to be a major cause of false positives and false negatives in select enzymatic high-throughput screening assays. The goal of this study was to investigate the impact of drug-rich aggregates on in vitro drug screening metabolism assays. METHODS: Cilnidipine was selected as an aggregate former and its impact on drug metabolism was evaluated against rCYP2D6, rCYP1A2, rCYP2C9 and human liver microsomes. RESULTS: The cilnidipine aggregates were shown to non-specifically inhibit multiple cytochrome P450 enzymes with an IC50 comparable with the IC50 of potent model inhibitors. CONCLUSIONS: This newly demonstrated mode of "promiscuous inhibition" is of great importance as it can lead to false positives during drug metabolism evaluations and thus it needs to be considered in the future to better predict in vivo drug-drug interactions.


Assuntos
Sistema Enzimático do Citocromo P-450/química , Di-Hidropiridinas/química , Microssomos Hepáticos/metabolismo , Proteínas Recombinantes/química , Carvedilol/química , Carvedilol/metabolismo , Coloides/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Diclofenaco/química , Diclofenaco/metabolismo , Di-Hidropiridinas/metabolismo , Interações de Medicamentos , Ensaios de Triagem em Larga Escala/métodos , Humanos , Concentração Inibidora 50 , Cinética , Taxa de Depuração Metabólica/efeitos dos fármacos , Fenacetina/química , Fenacetina/metabolismo , Proteínas Recombinantes/metabolismo , Solventes/química , Tamoxifeno/química , Tamoxifeno/metabolismo
9.
J Agric Food Chem ; 67(45): 12481-12495, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31630515

RESUMO

Biochanin A is a dietary isoflavone with multiple biological functions. Owing to a lack of comprehensive studies of biochanin A metabolism, this study was designed to further clarify the processes involved in biochanin A metabolism. In this study, ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) was utilized to characterize the metabolism of biochanin A in vivo and in vitro. As a result, 43 metabolites in rats, 22 metabolites in liver microsomes, and 18 metabolites in intestinal flora were elucidated, and 5 metabolites were identified by comparison with standards. Oxidation, demethylation, hydrogenation, internal hydrolysis, conjugation (e.g., glucuronidation, sulfonation, glucose conjugation, methylation, and acetylation), and their composite reactions were determined to be major processes involved in biochanin A biotransformation. The results contribute to a better understanding of the pharmacological mechanism of biochanin A and provide a basis for comprehension of the safety and toxicity of biochanin A.


Assuntos
Genisteína/metabolismo , Isoflavonas/metabolismo , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , Microbioma Gastrointestinal , Genisteína/química , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Isoflavonas/química , Masculino , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
10.
J Agric Food Chem ; 67(44): 12199-12207, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31595753

RESUMO

Salvianolic acid A (Sal A) has a wide range of pharmacological activities. To date, there have been no systematic and detailed metabolite research data of Sal A after oral administration in vitro and in vivo. In this study, a rapid and systematic method based on ultrafast liquid chromatography-quadrupole-time-of-flight mass spectrometry was developed to detect metabolites of Sal A in vitro (human liver microsome, human intestinal microbiota, artificial gastric, and intestinal juice) and in vivo (urine, plasma, feces, and various organs collected after oral administration of Sal A to normal rats and pseudo-germ-free rats). A total of 26 metabolites of Sal A were characterized. These metabolites were formed through extensive metabolic reactions, such as hydroxylation, hydrogenation, and glucuronidation reactions. This study provides novel possibility for exploring the potential biological mechanism of Sal A, and aids the promotion of clinical application.


Assuntos
Ácidos Cafeicos/química , Ácidos Cafeicos/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Lactatos/química , Lactatos/metabolismo , Espectrometria de Massas/métodos , Salvia miltiorrhiza/química , Adulto , Animais , Feminino , Humanos , Masculino , Metaboloma , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Adulto Jovem
11.
Zhongguo Zhong Yao Za Zhi ; 44(14): 3064-3069, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31602854

RESUMO

This project is to investigate chemical compositions from the roots of Erythrina corallodendron. Through the methods of silica gel,ODS,Sephadex LH-20 column chromatography and preparative HPLC,15 compounds were isolated from the 95% ethanol extract of the roots of E. corallodendron. Based on spectroscopic techniques,the structures of these compounds were identified as 10,11-dioxoerythraline( 1),erythrinine( 2),erythraline( 3),11-methoxyerythraline( 4),cristanines B( 5),erythratine( 6),erysotrine( 7),medioresinol( 8),( ±)-ficusesquilignan A( 9),( +)-pinoresinol( 10),nicotinic acid( 11),dibutyl phthalate( 12),vanillic acid( 13),3-hydroxy-1-( 4-hydroxy-3-methoxyphenyl)-1-propanone( 14),and syringic acid( 15). Compounds 8-10 are isolated from genus Erythrina for the first time and all compounds are isolated from E. corallodendron for the first time. Furthermore,this paper screened the antioxidant and cytotoxic activities of the compounds using models of liver microsomal oxidation inhibition and MTT.


Assuntos
Erythrina/química , Compostos Fitoquímicos/análise , Raízes de Plantas/química , Antioxidantes/análise , Cromatografia Líquida de Alta Pressão , Microssomos Hepáticos/efeitos dos fármacos , Extratos Vegetais/análise
12.
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
13.
Int J Nanomedicine ; 14: 7095-7106, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564867

RESUMO

Background: Norisoboldine (NOR), the main isoquinoline alkaloid constituent in Radix Linderae, was demonstrated to have an outstanding anti-arthritis activity. However, a poor oral bioavailability of NOR creates a barrier for its development and application. Methods: A new self-nanoemulsifying drug delivery system (SNEDDS) loaded with the phospholipid complex (PC) was designed to improve the oral bioavailability of NOR. NOR-PC was prepared by solvent evaporation method with a mixture of phospholipid and NOR at a mass ratio of 3:1. The property of PC is to improve the liposolubility of NOR, and made PC embedded in the drug delivery system. The physicochemical property of NOR-PC was characterized by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). According to the ability to dissolve NOR-PC, the oil and cosurfactant were chosen. The surfactant was selected based on its emulsification efficiency in SNEDDS. Pseudo-ternary phase diagram was created to select the best formulation of NOR-PC-SNEDDS, and the pharmacokinetic parameters were detected in rats. In addition, intestinal lymphatic transport and liver microsome experiment were studied to gain insight into the mechanism for NOR-PC-SNEDDS increasing the oral bioavailability of NOR. Results: Solubility detection showed that the PC significantly improved the liposolubility of NOR. NOR-PC-SNEDDS was prepared using NOR-PC, Ethyl oleate, Labrasol, Cremophor EL and transcutol HP at a weight ratio of 1:2:3.36:2.24:2.4 (w/w/w/w/w). The particle size and zeta potential of NOR-PC-SNEDDS were 36.72±1.47 nm and -4.91±0.49 mV after dilution with distilled water at a ratio of 1:50 (w/w). The absolute bioavailability of NOR in the NOR-PC-SNEDDS group significantly increased and the value was 372% in relative to NOR group. Further studies indicated that NOR-PC-SNEDDS promoted the oral bioavailability of NOR by enhancing intestinal lymphatic absorption and inhibiting Phase II metabolism of NOR. Conclusion: These findings suggested that NOR-PC-SNEDDS was able to promote the oral bioavailability of NOR, which provided a foundation for the further development and application of NOR.


Assuntos
Absorção Fisiológica , Alcaloides/farmacologia , Sistemas de Liberação de Medicamentos , Emulsões/química , Nanopartículas/química , Fosfolipídeos/química , Administração Oral , Alcaloides/sangue , Alcaloides/química , Alcaloides/farmacocinética , Animais , Varredura Diferencial de Calorimetria , Intestinos/fisiologia , Sistema Linfático/fisiologia , Masculino , Desintoxicação Metabólica Fase II , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Transição de Fase , Ratos Sprague-Dawley , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Tensoativos/química , Termodinâmica , Fatores de Tempo
14.
Chem Commun (Camb) ; 55(89): 13362-13365, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31631195

RESUMO

Rule-of-five parameters and membrane permeabilities have been routinely used to guide development of orally bioavailabile drugs. Here we compare enantiomeric pairs of cyclic hexapeptides with identical rule-of-five parameters and membrane permeabilities. For each enantiomeric pair, the isomer with more l- than d-amino acids is much more orally bioavailable in rats, more metabolically stable to rat liver microsomes, and cleared more slowly in vivo.


Assuntos
Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Conformação Molecular , Peptídeos Cíclicos/administração & dosagem , Ratos , Estereoisomerismo
15.
J Agric Food Chem ; 67(42): 11650-11656, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31554401

RESUMO

Occurring in hops (Humulus lupulus) and beer as a racemic mixture, (2R,2S)-8-prenylnaringenin (8-PN) is a potent phytoestrogen in hop dietary supplements used by women as alternatives to conventional hormone therapy. With a half-life exceeding 20 h, 8-PN is excreted primarily as 8-PN-7-O-glucuronide or 8-PN-4'-O-glucuronide. Human liver microsomes and 11 recombinant human UDP-glucuronosyltransferases (UGTs) were used to catalyze the formation of the two oxygen-linked glucuronides of purified (2R)-8-PN and (2S)-8-PN, which were subsequently identified using mass spectrometry and nuclear magnetic resonance spectroscopy. Formation of (2R)- and (2S)-8-PN-7-O-glucuronides predominated over the 8-PN-4'-O-glucuronides except for intestinal UGT1A10, which formed more (2S)-8-PN-4'-O-glucuronide. (2R)-8-PN was a better substrate for all 11 UGTs except for UGT1A1, which formed more of both (2S)-8-PN glucuronides than (2R)-8-PN glucuronides. Although several UGTs conjugated both enantiomers of 8-PN, some conjugated just one enantiomer, suggesting that human phenotypic variation might affect the routes of metabolism of this chiral estrogenic constituent of hops.


Assuntos
Flavanonas/química , Glucuronídeos/química , Glucuronosiltransferase/química , Extratos Vegetais/química , Biocatálise , Flavanonas/metabolismo , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Humanos , Humulus/química , Humulus/metabolismo , Espectrometria de Massas , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Extratos Vegetais/metabolismo , Estereoisomerismo
16.
Environ Sci Technol ; 53(20): 12081-12090, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31532198

RESUMO

Humans are inevitably exposed to a complex mixture of organic contaminants (i.e., xenobiotics) through diet, environment, and behavior. Biotransformation makes key contributions to the elimination of xenobiotics and greatly mediates the toxicity. However, most biotransformation studies were conducted using individual chemical, and whether coexposure of multiple environmental chemicals will affect each other's fate in the human body is still in its infancy. In this study, bisphenol A (BPA) was selected as a model compound. Its biotransformation was investigated under single exposure/coexposure to other phenolic xenobiotics (triclosan, tetrabromobisphenol A, and bisphenol S) in liver microsome and cell models. The result shows that binary exposures exhibit significant inhibitory effects on the BPA metabolism, especially the sulfate conjugation. In combination of analysis on inhibition models and enzyme activity, the inhibition effect was suggested to be primarily driven by competition for metabolizing enzymes. A mixture with 22 phenolic chemicals was further examined to disrupt BPA at various human-relevant levels. Again, the result demonstrates significant inhibition on the BPA metabolism, indicating the possible natural existence of our finding. Overall, our results show that biotransformation of phenolic xenobiotics can be significantly altered by coexposure, which provides referential evidence on underestimated risks of simultaneous exposure to environmental toxicants.


Assuntos
Triclosan , Xenobióticos , Biotransformação , Humanos , Microssomos Hepáticos
17.
BMC Complement Altern Med ; 19(1): 240, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484532

RESUMO

BACKGROUND: Major depression is an important complication in patients with breast cancer, but is an underrecognized and undertreated condition in this population. The Baihe Zhimu Tang (BZ formula) is a traditional Chinese formula consisting of Lilium brownii var. viridulum Baker (L. brownii) and Anemarrhena asphodeloides (A. asphodeloides) Bunge that is used for the treatment of depression. However, the interaction between tamoxifen and BZ formula is frequently overlooked by traditional and alternative medical doctors. In the present study, the influence of BZ formula on the effectiveness of tamoxifen in breast cancer in mice and the effects of tamoxifen on the antidepressant effect of BZ formula and its major components mangiferin and timosaponin BII in mice were investigated. METHODS: Identification of the major components of BZ formula was performed using fast HPLC-tandem mass spectrometry (HPLC-MS/MS). The main flavonoids and saponins in A. asphodeloides were determined by HPLC-UV and HPLC-ELSD, separately. The antidepressant efficacy of BZ formula was evaluated using a mouse tail-suspension test. The effects of BZ formula on the antineoplastic activity of tamoxifen were performed in a mouse xenograft model of human breast cancer MCF-7 cells. P450 activity was determined using microsomal incubations by HPLC-MS/MS. Measurement of serum concentrations of tamoxifen and its metabolites was used by HPLC-MS/MS. RESULTS: BZ formula attenuated the effectiveness of tamoxifen treatment of breast cancer and reduced the concentrations of endoxifen and 4-OH-tamoxifen in tumor-bearing mice. Of two of the major components of BZ formula, the antidepressant effect of mangiferin, but not timosaponin BII, was significantly inhibited by tamoxifen in mice. BZ formula and its component mangiferin also significantly inhibited CYP450 enzyme activity in rat liver microsomes. CONCLUSION: BZ formula attenuated the effectiveness of tamoxifen in treatment of breast cancer in mice by influencing CYP450 enzymes. The present study laid a foundation for the treatment of patients with breast cancer and depression by BZ formula or other Chinese herbal formulas containing A. asphodeloides.


Assuntos
Antineoplásicos Hormonais/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Mamárias Experimentais/metabolismo , Tamoxifeno/farmacologia , Animais , Antineoplásicos Hormonais/farmacocinética , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Depressão/metabolismo , Interações de Medicamentos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Feminino , Humanos , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Tamoxifeno/farmacocinética
18.
Nat Biotechnol ; 37(9): 1038-1040, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31477924

RESUMO

We have developed a deep generative model, generative tensorial reinforcement learning (GENTRL), for de novo small-molecule design. GENTRL optimizes synthetic feasibility, novelty, and biological activity. We used GENTRL to discover potent inhibitors of discoidin domain receptor 1 (DDR1), a kinase target implicated in fibrosis and other diseases, in 21 days. Four compounds were active in biochemical assays, and two were validated in cell-based assays. One lead candidate was tested and demonstrated favorable pharmacokinetics in mice.


Assuntos
Aprendizado Profundo , Receptor com Domínio Discoidina 1/antagonistas & inibidores , Receptor com Domínio Discoidina 1/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Receptor com Domínio Discoidina 1/genética , Cães , Inibidores Enzimáticos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Ratos
19.
Food Chem Toxicol ; 133: 110792, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31472229

RESUMO

Parabens are widely used as preservatives in personal care products, medicines and foods, resulting in substantial human exposures, even though some harmful effects, such as endocrine-disrupting activity, have been reported. Pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPARα), which are members of the nuclear receptor superfamily, regulate the metabolism of endogenous substrates including hormones. Therefore, we hypothesized that parabens may alter hormone-metabolizing activities by acting on these receptors, and such changes could contribute to the endocrine-disrupting activity. To test this idea, we systematically examined the effects of 17 parabens on these receptors using reporter gene assays. Nine parabens significantly activated human and rat PXR. Parabens with C2-C5 (linear and branched) side chains were most active. Butylparaben and isobutylparaben also significantly activated rat CAR. We found that long-side-chain (C7-C12) parabens showed up to 2-fold activation of PPARα at 10 µM. Furthermore, pentylparaben and hexylparaben showed rat PXR antagonistic activity and rat CAR inverse agonistic activity. The activity of butylparaben towards PXR and CAR was lost after carboxylesterase-mediated metabolism. These findings confirm that parabens influence the activities of PXR, CAR and PPARα, and thus have the potential to contribute to endocrine disruption by altering hormone metabolism.


Assuntos
PPAR alfa/metabolismo , Parabenos/farmacologia , Receptor de Pregnano X/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Ativação Transcricional/efeitos dos fármacos , Animais , Agonismo Inverso de Drogas , Humanos , Masculino , Microssomos Hepáticos/metabolismo , PPAR alfa/agonistas , PPAR alfa/genética , Parabenos/metabolismo , Receptor de Pregnano X/antagonistas & inibidores , Receptor de Pregnano X/genética , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/genética
20.
Molecules ; 24(16)2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430908

RESUMO

APINACA (known as AKB48, N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide), an indazole carboxamide synthetic cannabinoid, has been used worldwide as a new psychoactive substance. Drug abusers take various drugs concomitantly, and therefore, it is necessary to characterize the potential of APINACA-induced drug-drug interactions due to the modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of APINACA on eight major human cytochrome P450s (CYPs) and six uridine 5'-diphospho-glucuronosyltransferases (UGTs) in human liver microsomes, as well as on the transport activities of six solute carrier transporters and two efflux transporters in transporter-overexpressed cells, were investigated. APINACA exhibited time-dependent inhibition of CYP3A4-mediated midazolam 1'-hydroxylation (Ki, 4.5 µM; kinact, 0.04686 min-1) and noncompetitive inhibition of UGT1A9-mediated mycophenolic acid glucuronidation (Ki, 5.9 µM). APINACA did not significantly inhibit the CYPs 1A2, 2A6, 2B6, 2C8/9/19, or 2D6 or the UGTs 1A1, 1A3, 1A4, 1A6, or 2B7 at concentrations up to 100 µM. APINACA did not significantly inhibit the transport activities of organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT)1, OCT2, P-glycoprotein, or breast cancer resistance protein at concentrations up to 250 µM. These data suggest that APINACA can cause drug interactions in the clinic via the inhibition of CYP3A4 or UGT1A9 activities.


Assuntos
Transporte Biológico/efeitos dos fármacos , Canabinoides/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Glucuronosiltransferase/antagonistas & inibidores , Linhagem Celular , Interações de Medicamentos , Células HEK293 , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Transportadores de Ânions Orgânicos/metabolismo
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