Title: Structural Insights into the Interaction of Cytochrome P450 3A4 with Suicide Substrates: Mibefradil, Azamulin and 6',7'-Dihydroxybergamottin.
Authors: Sevrioukova, Irina F
Published In Int J Mol Sci, (2019 Aug 30)
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insights into the interaction of CYP3A4 with three suicide substrates: mibefradil, an antihypertensive drug quickly withdrawn from the market; a semi-synthetic antibiotic azamulin; and a natural furanocoumarin, 6',7'-dihydroxybergamottin.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.
PubMed ID: 31480231
MeSH Terms: Bridged-Ring Compounds/chemistry*; Bridged-Ring Compounds/metabolism*; Crystallography, X-Ray; Cytochrome P-450 CYP3A/chemistry*; Cytochrome P-450 CYP3A/metabolism*; Furocoumarins/chemistry*; Furocoumarins/metabolism*; Humans; Mibefradil/chemistry*; Mibefradil/metabolism*; Models, Molecular; Substrate Specificity; Triazoles/chemistry*; Triazoles/metabolism*