Summary of information on human CYP enzymes: human P450 metabolism data

Rendić, Slobodan

doi:10.1081/dmr-120001392

Cited by 733 publications

(503 citation statements)

References 942 publications

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“…Human CYP3A is one of the most important CYP isoforms involved in drug clearance and metabolized more than 50% of the drugs on the market [33] . Inhibition or stimulation of the catalytic activity of this enzyme could play a key role in clinical DDIs.…”

Section: Discussionmentioning

confidence: 99%

Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib

et al. 2011

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Aim: To ascertain the effects of erlotinib on CYP3A, to investigate the amplitude and kinetics of erlotinib-mediated inhibition of seven major CYP isoforms in human liver microsomes (HLMs) for evaluating the magnitude of erlotinib in drug-drug interaction in vivo. Methods: The activities of 7 major CYP isoforms (CYP1A2, CYP2A6, CYP3A, CYP2C9, CYP2D6, CYP2C8, and CYP2E1) were assessed in HLMs using HPLC or UFLC analysis. A two-step incubation method was used to examine the time-dependent inhibition of erlotinib on CYP3A.Results: The activity of CYP2C8 was inhibited with an IC 50 value of 6.17±2.0 μmol/L. Erlotinib stimulated the midazolam 1′-hydroxy reaction, but inhibited the formation of 6β-hydroxytestosterone and oxidized nifedipine. Inhibition of CYP3A by erlotinib was substratedependent: the IC 50 values for inhibiting testosterone 6β-hydroxylation and nifedipine metabolism were 31.3±8.0 and 20.5±5.3 μmol/L, respectively. Erlotinib also exhibited the time-dependent inhibition on CYP3A, regardless of the probe substrate used: the value of K I and k inact were 6.3 μmol/L and 0.035 min -1 for midazolam; 9.0 μmol/L and 0.045 min -1 for testosterone; and 10.1 μmol/L and 0.058 min -1 for nifedipine. Conclusion: The inhibition of CYP3A by erlotinib was substrate-dependent, while its time-dependent inhibition on CYP3A was substrateindependent. The time-dependent inhibition of CYP3A may be a possible cause of drug-drug interaction, suggesting that attention should be paid to the evaluation of erlotinib's safety, especially in the context of combination therapy.

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Section: Discussionmentioning

confidence: 99%

Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib

et al. 2011

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“…It is found in the liver and it is estimated to metabolize one third of the marketed drugs. [6] In the CYP family, the promiscuous 3A4 isoform is the one offering the largest diversity of substrates. It was shown using molecular dynamics simulations on the human CYPs 3A4, 2C9, and 2A6, that the malleability correlates with the substrate specificity.…”

Section: Introductionmentioning

confidence: 99%

The Cytochrome P450 3A4 has three Major Conformations: New Clues to Drug Recognition by this Promiscuous Enzyme

Benkaidali

André

Moroy

et al. 2017

Molecular Informatics

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Dedication: This paper is dedicated to the memory of Professor Boubekeur Maouche. Abstract:We computed the channels of the 3A4 isoform of the cytochrome P450 3A4 (CYP) on the basis of 24 crystal structures extracted from the Protein Data Bank (PDB). We identified three major conformations (denoted C, O1 and O2) using an enhanced version of the CCCPP software that we developed for the present work, while only two conformations (C and O 2 ) are considered in the literature.We established the flowchart of definition of these three conformations in function of the structural and physicochemical parameters of the ligand. The channels are characterized with qualitative and quantitative parameters, and not only with their surrounding secondary structures as it is usually done in the literature

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“…CYP2D6 is an especially good model system for our studies, because of its broad substrate specificity. Over 400 ligands have recently been reported 6 for CYP2D6, of which ∼60% are substrates and ∼40% are inhibitors. To accommodate such a wide range of ligands must require significant binding site flexibility and malleability, which is not easily modeled using most current docking approaches.…”

Section: Introductionmentioning

confidence: 99%

Synergistic Use of Compound Properties and Docking Scores in Neural Network Modeling of CYP2D6 Binding: Predicting Affinity and Conformational Sampling

Bazeley

Prithivi

Struble

et al. 2006

J. Chem. Inf. Model.

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Cytochrome P450 2D6 (CYP2D6) is used to develop an approach for predicting affinity and relevant binding conformation(s) for highly flexible binding sites. The approach combines the use of docking scores and compound properties as attributes in building a neural network (NN) model. It begins by identifying segments of CYP2D6 that are important for binding specificity, based on structural variability among diverse CYP enzymes. A family of distinct, low-energy conformations of CYP2D6 are generated using simulated annealing (SA) and a collection of 82 compounds with known CYP2D6 affinities are docked. Interestingly, docking poses are observed on the backside of the heme as well as in the known actiVe site. Docking scores for the actiVe site binders, along with compound-specific attributes, are used to train a neural network model to properly bin compounds as strong binders, moderate binders, or nonbinders. Attribute selection is used to preselect the most important scores and compound-specific attributes for the model. A prediction accuracy of 85 ( 6% is achieved. Dominant attributes include docking scores for three of the 20 conformations in the ensemble as well as the compound's formal charge, number of aromatic rings, and AlogP. Although compound properties were highly predictive attributes (12% improvement over baseline) in the NN-based prediction of CYP2D6 binders, their combined use with docking score attributes is synergistic (net increase of 23% above baseline). Beyond prediction of affinity, attribute selection provides a way to identify the most relevant protein conformation(s), in terms of binding competence. In the case of CYP2D6, three out of the ensemble of 20 SA-generated structures are found to be the most predictive for binding.

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Summary of information on human CYP enzymes: human P450 metabolism data

Cited by 733 publications

References 942 publications

Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib

Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib

The Cytochrome P450 3A4 has three Major Conformations: New Clues to Drug Recognition by this Promiscuous Enzyme

Synergistic Use of Compound Properties and Docking Scores in Neural Network Modeling of CYP2D6 Binding: Predicting Affinity and Conformational Sampling

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