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Title: Structural Insights into the Interaction of Cytochrome P450 3A4 with Suicide Substrates: Mibefradil, Azamulin and 6',7'-Dihydroxybergamottin

Abstract

Human cytochrome P450 3A4 (CYP3A4) is the most important drug-metabolizing enzyme. Some drugs and natural compounds can act as suicide (mechanism-based) inactivators of CYP3A4, leading to unanticipated drug-drug interactions, toxicity and therapeutic failures. Despite significant clinical and toxicological implications, the mechanism-based inactivation remains incompletely understood. This study provides the first direct insights into the interaction of CYP3A4 with three suicide substrates: mibefradil, an antihypertensive drug quickly withdrawn from the market; a semi-synthetic antibiotic azamulin; and a natural furanocoumarin, 6',7'-dihydroxybergamottin. Novel structural findings help better understand the suicide substrate binding and inhibitory mechanism, and can be used to improve the predictability of the binding ability, metabolic sites and inhibitory/inactivation potential of newly developed drugs and other chemicals relevant to public health.

Authors:
ORCiD logo [1]
  1. Univ. of California, Irvine, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1628386
Grant/Contract Number:  
AC02-05CH11231; AC02-76SF00515; P41GM103393
Resource Type:
Accepted Manuscript
Journal Name:
International Journal of Molecular Sciences (Online)
Additional Journal Information:
Journal Name: International Journal of Molecular Sciences (Online); Journal Volume: 20; Journal Issue: 17; Journal ID: ISSN 1422-0067
Publisher:
MDPI
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biochemistry & Molecular Biology; Chemistry; CYP3A4; mechanism-based inhibitor; crystal structure

Citation Formats

Sevrioukova, Irina F. Structural Insights into the Interaction of Cytochrome P450 3A4 with Suicide Substrates: Mibefradil, Azamulin and 6',7'-Dihydroxybergamottin. United States: N. p., 2019. Web. https://doi.org/10.3390/ijms20174245.
Sevrioukova, Irina F. Structural Insights into the Interaction of Cytochrome P450 3A4 with Suicide Substrates: Mibefradil, Azamulin and 6',7'-Dihydroxybergamottin. United States. https://doi.org/10.3390/ijms20174245
Sevrioukova, Irina F. Fri . "Structural Insights into the Interaction of Cytochrome P450 3A4 with Suicide Substrates: Mibefradil, Azamulin and 6',7'-Dihydroxybergamottin". United States. https://doi.org/10.3390/ijms20174245. https://www.osti.gov/servlets/purl/1628386.
@article{osti_1628386,
title = {Structural Insights into the Interaction of Cytochrome P450 3A4 with Suicide Substrates: Mibefradil, Azamulin and 6',7'-Dihydroxybergamottin},
author = {Sevrioukova, Irina F.},
abstractNote = {Human cytochrome P450 3A4 (CYP3A4) is the most important drug-metabolizing enzyme. Some drugs and natural compounds can act as suicide (mechanism-based) inactivators of CYP3A4, leading to unanticipated drug-drug interactions, toxicity and therapeutic failures. Despite significant clinical and toxicological implications, the mechanism-based inactivation remains incompletely understood. This study provides the first direct insights into the interaction of CYP3A4 with three suicide substrates: mibefradil, an antihypertensive drug quickly withdrawn from the market; a semi-synthetic antibiotic azamulin; and a natural furanocoumarin, 6',7'-dihydroxybergamottin. Novel structural findings help better understand the suicide substrate binding and inhibitory mechanism, and can be used to improve the predictability of the binding ability, metabolic sites and inhibitory/inactivation potential of newly developed drugs and other chemicals relevant to public health.},
doi = {10.3390/ijms20174245},
journal = {International Journal of Molecular Sciences (Online)},
number = 17,
volume = 20,
place = {United States},
year = {2019},
month = {8}
}

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Cited by: 1 work
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Figures / Tables:

Figure 1 Figure 1: Chemical structures of the investigated compounds. Arrows indicate known sites of metabolism.

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    Works referencing / citing this record:

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