Gomisin A is a Novel Isoform-Specific Probe for the Selective Sensing of Human Cytochrome P450 3A4 in Liver Microsomes and Living Cells

Wu, Jingjing; Ge, Guang-Bo; He, Yuqi; Wang, Ping; Dai, Zhicheng; Ning, Jing; Hu, Lianghai; Yang, Ling

doi:10.1208/s12248-015-9827-4

Cited by 17 publications

(20 citation statements)

References 41 publications

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“…Although the levels of CYP3A4 in liver is generally higher than CYP3A5, but in some cases, the levels of CYP3A5 in given populations (such as African) may higher than that of CYP3A4 (Westlind-Johnsson et al, 2003; Lu et al, 2012). Given that the relative content of CYP3A5 to total hepatic CYP3A protein varies remarkably among individuals (17–50%), the contribution of CYP3A5 in BFT metabolism and the kinetic behaviors of BFT 5β-hydroxylation may be strongly affected by the expression and function of CYP3A5 (Wu et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 3A Enzymes Are Key Contributors for Hepatic Metabolism of Bufotalin, a Natural Constitute in Chinese Medicine Chansu

et al. 2019

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Bufotalin (BFT), one of the naturally occurring bufodienolides, has multiple pharmacological and toxicological effects including antitumor activity and cardiotoxicity. This study aimed to character the metabolic pathway(s) of BFT and to identify the key drug metabolizing enzyme(s) responsible for hepatic metabolism of BFT in human, as well as to explore the related molecular mechanism of enzymatic selectivity. The major metabolite of BFT in human liver microsomes (HLMs) was fully identified as 5β-hydroxylbufotalin by LC-MS/MS and NMR techniques. Reaction phenotyping and chemical inhibition assays showed that CYP3A4 and CYP3A5 were key enzymes responsible for BFT 5β-hydroxylation. Kinetic analyses demonstrated that BFT 5β-hydroxylation in both HLMs and human CYP3A4 followed the biphasic kinetics, while BFT 5β-hydroxylation in CYP3A5 followed substrate inhibition kinetics. Furthermore, molecular docking simulations showed that BFT could bind on two different ligand-binding sites on both CYP3A4 and CYP3A5, which partially explained the different kinetic behaviors of BFT in CYP3A4 and CYP3A5. These findings are very helpful for elucidating the phase I metabolism of BFT in human and for deeper understanding the key interactions between CYP3A enzymes and bufadienolides, as well as for the development of bufadienolide-type drugs with improved pharmacokinetic and safety profiles.

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Section: Discussionmentioning

confidence: 99%

Cytochrome P450 3A Enzymes Are Key Contributors for Hepatic Metabolism of Bufotalin, a Natural Constitute in Chinese Medicine Chansu

et al. 2019

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“…The intrinsic clearance ( CL int ) of schisandrin A was obtained from re‐analysis of its depletion in HLM, while contribution of CYP3A enzymes ( f m,CYP3A = 0.76) was estimated from the percent of inhibition by ketoconazole 11 . CL int of schisantherin A 9 and schisandrol B 12 were also specified based on their metabolic pathways 11 . The mechanism‐based inhibition and induction of CYP3A4 following the chronic exposure to S. sphenanthera extract were modelled by an enzyme turnover model, depicted by an increase in degradation and synthesis of the active enzyme, respectively 48,50 .…”

Section: Methodsmentioning

confidence: 99%

“… k K i was derived from IC 50 towards metabolism of midazolam in recombinant CYP3A4, assuming a competitive inhibition 12 …”

Section: Introductionmentioning

confidence: 99%

Potential for pharmacokinetic interactions between Schisandra sphenanthera and bosutinib, but not imatinib: in vitro metabolism study combined with a physiologically‐based pharmacokinetic modelling approach

Adiwidjaja

Boddy

McLachlan

2020

Brit J Clinical Pharma

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Aims This study aimed to investigate the potential interaction between Schisandra sphenanthera, imatinib and bosutinib combining in vitro and in silico methods. Methods In vitro metabolism of imatinib and bosutinib using recombinant enzymes and human liver microsomes were investigated in the presence and absence of Schisandra lignans. Physiologically‐based pharmacokinetic (PBPK) models for the lignans accounting for reversible and mechanism‐based inhibitions and induction of CYP3A enzymes were built in the Simcyp Simulator (version 17) and evaluated for their capability to predict interactions with midazolam and tacrolimus. Their potential effect on systemic exposures of imatinib and bosutinib were predicted using PBPK in silico simulations. Results Schisantherin A and schisandrol B, but not schisandrin A, potently inhibited CYP3A4‐mediated metabolism of imatinib and bosutinib. All three compounds showed a strong reversible inhibition on CYP2C8 enzyme with ki of less than 0.5 μmol L−1. The verified PBPK models were able to describe the increase in systemic exposure of midazolam and tacrolimus due to co‐administration of S. sphenanthera, consistent with the reported changes in the corresponding clinical interaction study (AUC ratio of 2.0 vs 2.1 and 2.4 vs 2.1, respectively). The PBPK simulation predicted that at recommended dosing regimens of S. sphenanthera, co‐administration would result in an increase in bosutinib exposure (AUC ratio 3.0) but not in imatinib exposure. Conclusion PBPK models for Schisandra lignans were successfully developed. Interaction between imatinib and Schisandra lignans was unlikely to be of clinical importance. Conversely, S. sphenanthera at a clinically‐relevant dose results in a predicted three‐fold increase in bosutinib systemic exposure.

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“…To illustrate the molecular mechanism of the selective catalysis of CYP3A5 for SE, docking simulation was employed and performed using the knowledge-based homology modeling package from Advanced Protein Modeling (APM) that was distributed within SYBYL (X-1.1). The homology model of CYP3A5 was constructed based on the template structure of CYP3A4 (PDB ID: 3TJS) as previously described [15]. With the established 3D-structure of CYP3A5 as well as the crystal structure of CYP3A4, the bioactive binding conformations of GC and GG were respectively generated using Surflex-Dock and were evaluated by an empirical function ChemScore, one of the most suitable scoring functions for P450s.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of human CYP3A4 and CYP3A5 enzymes by gomisin C and gomisin G, two lignan analogs derived from Schisandra chinensis

Zhao

Sun

et al. 2017

Fitoterapia

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Gomisin C (GC) and gomisin G (GG) are two lignan analogs isolated from the Traditional Chinese Medicine Schisandra chinensis which possesses multiple pharmacological activities. However, the potential herb-drug interactions (HDI) between these lignans and other drugs through inhibiting human cytochrome P450 3A4 (CYP3A4) and CYP3A5 remains unclear. In the present study, the inhibitory action of GC and GG on CYP3A4 and CYP3A5 were investigated. The results demonstrated that both GC and GG strongly inhibited CYP3A-mediated midazolam 1'-hydroxylation, nifedipine oxidation and testosterone 6β-hydroxylation. Notably, the inhibitory intensity of GC towards CYP3A4 was stronger than CYP3A5 when using midazolam and nifedipine as substrates. While inhibition of GC towards CYP3A5 was weaker than CYP3A4 when using testosterone as substrate. In contrast, GG showed a stronger inhibitory activity on CYP3A5 than CYP3A4 without substrate-dependent behavior. In addition, docking simulations indicated that the π-π interaction between CYP3A4 and GC, and hydrogen-bond interaction between CYP3A5 and GG might result in their different inhibitory actions. Furthermore, the AUC of drugs metabolized by CYP3A was estimated to increase by 8%-321% and 2%-3190% in the presence of GC and GG, respectively. These findings strongly suggested that GC and GG showed high HDI potentials, and the position of methylenedioxy group determined their different inhibitory effect towards CYP3A4 and CYP3A5, which are of significance for the application of Schisandra chinensis-containing herbs.

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Gomisin A is a Novel Isoform-Specific Probe for the Selective Sensing of Human Cytochrome P450 3A4 in Liver Microsomes and Living Cells

Cited by 17 publications

References 41 publications

Cytochrome P450 3A Enzymes Are Key Contributors for Hepatic Metabolism of Bufotalin, a Natural Constitute in Chinese Medicine Chansu

Cytochrome P450 3A Enzymes Are Key Contributors for Hepatic Metabolism of Bufotalin, a Natural Constitute in Chinese Medicine Chansu

Potential for pharmacokinetic interactions between Schisandra sphenanthera and bosutinib, but not imatinib: in vitro metabolism study combined with a physiologically‐based pharmacokinetic modelling approach

Inhibition of human CYP3A4 and CYP3A5 enzymes by gomisin C and gomisin G, two lignan analogs derived from Schisandra chinensis

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