Abstract:
BACKGROUND:Cytochrome P450 2E1 (CYP2E1) plays a central role in the metabolism and metabolic activation of a large number of small, mostly xenobiotic compounds. These qualities distinguish CYP2E1 from traditional enzymes and pose significant challenges to understanding the role and consequences of CYP2E1-mediated metabolism. OBJECTIVE:This review discusses recent advances in kinetic profiling, quantitative structure-activity relationships and structural studies that have furthered the development of tools to interpret and predict CYP2E1 metabolism. METHODS:Analysis of kinetic profiles by specific mechanisms produces important parameters describing specificity, stoichiometry and metabolism of molecules. Quantitative structure-activity relationships reveal a more specific basis for molecular recognition by CYP2E1. The corresponding protein structures imparting these interactions are the focus of chemical modifications, site-directed mutagenesis and homology modeling studies. RESULTS:Compilation of kinetic profiling for CYP2E1 substrates established the selectivity for small substrates, whose characteristics could be generalized in parameters for hydrophobicity and steric properties as determined by quantitative structure-activity relationships. The possibility of an effector site for monocyclic compounds added an interesting variable to these modeling efforts. Various structural studies identified important residues contributing to binding and catalysis as well as the volume and location of the active site relative to the heme moiety. Pressure and carbon monoxide-binding experiments also demonstrated the inherent conformational flexibility of CYP2E1 that may contribute to rate-limiting steps during catalytic turnover. CONCLUSION:Although combinations of these approaches have reinforced important observations, more work is needed to verify findings and seek broader impacts for various interpretative and predictive tools.
journal_name
Expert Opin Drug Metab Toxicoljournal_title
Expert opinion on drug metabolism & toxicologyauthors
Miller GPdoi
10.1517/17425255.4.8.1053subject
Has Abstractpub_date
2008-08-01 00:00:00pages
1053-64issue
8eissn
1742-5255issn
1744-7607journal_volume
4pub_type
杂志文章,评审abstract:BACKGROUND:Sertindole is a second-generation antipsychotic recently reintroduced in the market for the treatment of schizophrenia after a reevaluation of its risks and benefits. OBJECTIVE:This article provides an overview of the pharmacological properties of sertindole as well as of its efficacy, tolerability and safe...
journal_title:Expert opinion on drug metabolism & toxicology
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doi:10.1517/17425255.4.5.629
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abstract:INTRODUCTION:Drug-disease interactions include the impact of a drug and a particular disease condition on each other. However, the current practice in addressing drug-disease interaction is unbalanced and mostly limited to how the drug worsens the disease or health condition. AREAS COVERED:Aspirin and gastric ulcer in...
journal_title:Expert opinion on drug metabolism & toxicology
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journal_title:Expert opinion on drug metabolism & toxicology
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journal_title:Expert opinion on drug metabolism & toxicology
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journal_title:Expert opinion on drug metabolism & toxicology
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abstract::It has increasingly been recognized that few molecules move across the cell membrane without the assistance of transporter proteins. Large superfamilies of transporter proteins have been identified in every living cell, including microorganisms and mitochondria. This report reviews the role of transporters in physiolo...
journal_title:Expert opinion on drug metabolism & toxicology
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journal_title:Expert opinion on drug metabolism & toxicology
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journal_title:Expert opinion on drug metabolism & toxicology
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更新日期:2006-10-01 00:00:00
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journal_title:Expert opinion on drug metabolism & toxicology
pub_type: 杂志文章,评审
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更新日期:2019-06-01 00:00:00
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journal_title:Expert opinion on drug metabolism & toxicology
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doi:10.1517/17425255.2013.802306
更新日期:2013-08-01 00:00:00
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journal_title:Expert opinion on drug metabolism & toxicology
pub_type: 杂志文章,评审
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更新日期:2017-11-01 00:00:00
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journal_title:Expert opinion on drug metabolism & toxicology
pub_type: 杂志文章,评审
doi:10.1517/17425255.2013.823157
更新日期:2013-11-01 00:00:00
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journal_title:Expert opinion on drug metabolism & toxicology
pub_type: 杂志文章,评审
doi:10.1080/17425255.2019.1588885
更新日期:2019-04-01 00:00:00
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journal_title:Expert opinion on drug metabolism & toxicology
pub_type: 杂志文章,评审
doi:10.1517/17425255.4.10.1307
更新日期:2008-10-01 00:00:00
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journal_title:Expert opinion on drug metabolism & toxicology
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更新日期:2009-03-01 00:00:00
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更新日期:2018-10-01 00:00:00
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更新日期:2018-08-01 00:00:00
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journal_title:Expert opinion on drug metabolism & toxicology
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更新日期:2015-01-01 00:00:00
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journal_title:Expert opinion on drug metabolism & toxicology
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pub_type: 杂志文章
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更新日期:2016-11-01 00:00:00
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pub_type: 杂志文章,评审
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更新日期:2008-09-01 00:00:00