In silico metabolism studies of dietary flavonoids by CYP1A2 and CYP2C9

Sousa, Mariana C.; Braga, Rodolpho C.; Cintra, Bertilha Alves Santana; Oliveira, Valéria de; Andrade, Carolina Horta

doi:10.1016/j.foodres.2012.09.027

Cited by 27 publications

(12 citation statements)

References 46 publications

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“…Chaichit et al (2014) investigated the binding of chrysin to CYP2C9; they also identified F114, L208, and A297 as key interacting amino acids. A previous in silico study of flavonoid-CYP2C9 interactions (Sousa et al, 2013) suggests the importance of N474 and S209; we have the same findings regarding C7S (Fig. 3C).…”

Section: Discussionsupporting

confidence: 89%

“…3C). The binding free energies of naringenin (25.98 kcal/mol) and quercetin (26.77 kcal/mol) with CYP2C9 (Sousa et al, 2013) showed good correlation with our data. Furthermore, previous in silico studies with bavachin also suggest that the binding position of flavonoids is close to the heme iron in both CYP2C9 and 2C19 (Wang et al, 2018), as is demonstrated with chrysin in Figure 3, A and D. Investigation of corylifol A showed the importance of amino acid residues L208, A297, and T301 in the interaction with CYP2C9 enzyme, and the involvement of F100, F114, N204, L237, G296, L366, and F476 has been reported with CYP2C19 (Wang et al, 2018), showing good correlations with our observations.…”

Section: Discussionsupporting

confidence: 84%

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Effects of Chrysin and Its Major Conjugated Metabolites Chrysin-7-Sulfate and Chrysin-7-Glucuronide on Cytochrome P450 Enzymes and on OATP, P-gp, BCRP, and MRP2 Transporters

et al. 2020

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Chrysin is an abundant flavonoid in nature, and it is also contained by several dietary supplements. Chrysin is highly biotransformed in the body, during which conjugated metabolites chrysin-7-sulfate and chrysin-7-glucuronide are formed. These conjugates appear at considerably higher concentrations in the circulation than the parent compound. Based on previous studies, chrysin can interact with biotransformation enzymes and transporters; however, the interactions of its metabolites have been barely examined. In this in vitro study, the effects of chrysin, chrysin-7-sulfate, and chrysin-7glucuronide on cytochrome P450 enzymes (2C9, 2C19, 3A4, and 2D6) as well as on organic anion-transporting polypeptides (OATPs; 1A2, 1B1, 1B3, and 2B1) and ATP binding cassette [P-glycoprotein, multidrug resistance-associated protein 2, and breast cancer resistance protein (BCRP)] transporters were investigated. Our observations revealed that chrysin conjugates are strong inhibitors of certain biotransformation enzymes (e.g., CYP2C9) and transporters (e.g., OATP1B1, OATP1B3, OATP2B1, and BCRP) examined. Therefore, the simultaneous administration of chrysin-containing dietary supplements with medications needs to be carefully considered due to the possible development of pharmacokinetic interactions. SIGNIFICANCE STATEMENT Chrysin-7-sulfate and chrysin-7-glucuronide are the major metabolites of flavonoid chrysin. In this study, we examined the effects of chrysin and its conjugates on cytochrome P450 enzymes and on organic anion-transporting polypeptides and ATP binding cassette transporters (P-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated protein 2). Our results demonstrate that chrysin and/or its conjugates can significantly inhibit some of these proteins. Since chrysin is also contained by dietary supplements, high intake of chrysin may interrupt the transport and/or the biotransformation of drugs.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 84%

Effects of Chrysin and Its Major Conjugated Metabolites Chrysin-7-Sulfate and Chrysin-7-Glucuronide on Cytochrome P450 Enzymes and on OATP, P-gp, BCRP, and MRP2 Transporters

et al. 2020

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“…3). Previous studies have shown that CYP1A2 is a major contributor in the hydroxylation of flavonoids [16]. The affinity for CYP1A2-mediated oxidative pathways appeared lower (K m : 648.5 µM) than that of jaceosidin (a flavone catalyzed by CYP1A2) (K m : 95.9-101 µM) (l " Fig.…”

Section: Intmentioning

confidence: 92%

Metabolism of Chamaechromone In Vitro with Human Liver Microsomes and Recombinant Human Drug-Metabolizing Enzymes

et al. 2014

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Chamaechromone is a major component in the dried roots of Stellera chamaejasme with antihepatitis B virus and insecticidal activity. In this study, metabolic profiles of chamaechromone were investigated in human liver microsomes. One monohydroxide and two monoglucuronides of chamaechromone were identified. The enzyme kinetics for both hydroxylation and glucuronidation were fitted to the Michaelis-Menten equation. The hydroxylation of chamaechromone was inhibited by α-naphthoflavone, and predominantly catalyzed by recombinant human cytochrome P450 1A2, whereas the glucuronidation was inhibited by quercetin, 1-naphthol, and fluconazole, and mainly catalyzed by recombinant human UDP-glucuronosyltransferase 1A3, 1A7, 1A9, and 2B7. Key wordsStellera chamaejasme · Thymelaeaceae · chamaechromone · metabolite · in vitro · human liver microsomes · recombinant human enzymes Abbreviations ! CL int : intrinsic clearance DDI: drug-drug interaction hCYP: human cytochrome P450 HLMs: human liver microsomes hUGT: human UDP-glucuronosyltransferase K m : Michaelis constant UDPGA: UDP-glucuronic acid UPLC Q-TOF MS: ultra-performance liquid chromatography quadrupole-time-of-flight mass spectrometry V max : maximal velocity of formation Supporting information available online at http://www.thieme-connect.de/ejournals/toc/plantamedica Stellera chamaejasme L. (Thymelaeaceae) is a toxic perennial herb. Its root is known as Langdu and is described in the Chinese Pharmacopoeia [1] as having antiviral [2, 3], antitumor [4], antibacterial [5], immunomodulatory [6], and insecticidal effects [7, 8]. The use of Langdu along with various clinically prescribed drugs may result in a herb-drug interaction or Langdu toxicity [9]. Chamaechromone, a biflavone, is one of the major active constituents of the dried roots of S. chamaejasme [10]. The range of chamaechromoneʼs biological effects, such as its anti-HBV effect and insecticidal activity [2, 7], may explain the widespread use of Langdu. The pathways of biflavone metabolism are relatively limited compared to monomeric flavones [11]. Few studies have reported the metabolic characteristics of chamaechromone in human liver microsomes (HLMs). We estimated the oral bioavailability of chamaechromone in rats to be 8.9 % in our previous study [12]. Our follow-up study further established the metabolites of chamaechromone in the rat and in the rat liver S9 fraction [13]. However, humans and animals may display markedly different metabolic profiles with regard to the composition of different isoforms, and the expression and catalytic activities of drug-metabolizing enzymes [14]. Furthermore, HLMs and recombinant enzymes are useful in vitro tools for the prediction of drug-metabolism pathways in vivo in humans and for the identification of specific enzymes involved in these pathways. They also offer valuable insights into potential clinical drug-drug interactions [15]. They may also potentially reduce the use of animals and provide an easy drug-metabolizing enzyme assay protocol. In view of these advantages...

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“…A previsão é feita a partir das reações de fase 1 (oxidação e redução) e 2 (conjugação). Isto é possível através de buscas em data sets que contêm transformações metabólicas já reportadas na literatura científica e que acontecem em posições semelhantes às contidas nas moléculas estudadas com posterior análise estatística dos dados encontrados (TARCSAY et al, 2010;ADAMS, 2010;CARLSSON et al, 2010;BRAGA et al, 2012;PIECHOTA et al, 2013;SOUSA et al, 2013). O candidato a fármaco também foi submetido ao software Metaprint2D-React, disponível em http://www-metaprint2d.ch.cam.ac.uk/metaprint2d-react.…”

Section: Predição Do Metabolismo Utilizando O Software Metaprint2d-reactunclassified

PREDIÇÃO DO METABOLISMO DO CANDIDATO A FÁRMACO CINAMALDEÍDO: Uma abordagem in silico

Amorim

Pestana

Mendes³

2017

RCCP

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RESUMO:O objetivo do presente trabalho foi prever os prováveis sítios de metabolização e os prováveis metabólitos gerados do candidato a fármaco cinamaldeído (CNA) utilizando métodos in silico. Para isso, foram utilizadas duas plataformas virtuais, SMARTCyp e Metaprint2D-React. O SMARTCyp é uma plataforma online de previsão do metabolismo, ele usa algoritmos para fazer a previsão de metabolismo, porém estes algoritmos usam a energia de ativação do Citocromo P450. O Metaprint2D-React é uma plataforma virtual que usa algoritmos para prever os possíveis sítios de metabolismo de uma molécula. A previsão é feita a partir das reações de fase 1 (oxidação e Ressalta-se que estudos in silico são de grande importância quando associados a outros tipos de estudos na Pesquisa e Desenvolvimento P&D de fármacos. PALAVRAS-CHAVE: toxicologia computacional; toxicocinética; planejamento de fármacos. ABSTRACT:The aim of the present study was to predict the likely metabolic sites and the likely metabolites generated by the drug candidate cinnamaldehyde (CNA) using in silico methods. For

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In silico metabolism studies of dietary flavonoids by CYP1A2 and CYP2C9

Cited by 27 publications

References 46 publications

Effects of Chrysin and Its Major Conjugated Metabolites Chrysin-7-Sulfate and Chrysin-7-Glucuronide on Cytochrome P450 Enzymes and on OATP, P-gp, BCRP, and MRP2 Transporters

Effects of Chrysin and Its Major Conjugated Metabolites Chrysin-7-Sulfate and Chrysin-7-Glucuronide on Cytochrome P450 Enzymes and on OATP, P-gp, BCRP, and MRP2 Transporters

Metabolism of Chamaechromone In Vitro with Human Liver Microsomes and Recombinant Human Drug-Metabolizing Enzymes

PREDIÇÃO DO METABOLISMO DO CANDIDATO A FÁRMACO CINAMALDEÍDO: Uma abordagem in silico

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