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

2019 ◽  
Vol 20 (17) ◽  
pp. 4245 ◽  
Author(s):  
Irina F. Sevrioukova
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 3A4 ◽  
Drug Metabolizing Enzyme ◽  
Human Cytochrome ◽  
Suicide Substrate ◽  
Metabolizing Enzyme ◽  
Structural Insights ◽  
Suicide Mechanism ◽  
Important Drug ◽  
Suicide Substrates

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insights into the interaction of CYP3A4 with three suicide substrates: mibefradil, an antihypertensive drug quickly withdrawn from the market; a semi-synthetic antibiotic azamulin; and a natural furanocoumarin, 6′,7′-dihydroxybergamottin.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.

scholarly journals Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4

2020 ◽  
Author(s):  
Przemysław J. Danek ◽  
Agnieszka Basińska-Ziobroń ◽  
Jacek Wójcikowski ◽  
Władysława A. Daniel
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolizing Enzyme ◽  
Human Cytochrome ◽  
Metabolizing Enzyme

scholarly journals CYP3A4∗22 Genotyping in Clinical Practice: Ready for Implementation?

2021 ◽  
Vol 12 ◽  
Author(s):  
Tessa A. M. Mulder ◽  
Ruben A. G. van Eerden ◽  
Mirjam de With ◽  
Laure Elens ◽  
Dennis A. Hesselink ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Clinical Outcome ◽  
Clinical Utility ◽  
Current Knowledge ◽  
Cytochrome P450 3A4 ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme ◽  
Important Drug

Cytochrome P450 3A4 (CYP3A4) is the most important drug metabolizing enzyme in the liver, responsible for the oxidative metabolism of ∼50% of clinically prescribed drugs. Therefore, genetic variation in CYP3A4 could potentially affect the pharmacokinetics, toxicity and clinical outcome of drug treatment. Thus far, pharmacogenetics for CYP3A4 has not received much attention. However, the recent discovery of the intron 6 single-nucleotide polymorphism (SNP) rs35599367C > T, encoding the CYP3A4∗22 allele, led to several studies into the pharmacogenetic effect of CYP3A4∗22 on different drugs. This allele has a relatively minor allele frequency of 3-5% and an effect on CYP3A4 enzymatic activity. Thus far, no review summarizing the data published on several drugs is available yet. This article therefore addresses the current knowledge on CYP3A4∗22. This information may help in deciding if, and for which drugs, CYP3A4∗22 genotype-based dosing could be helpful in improving drug therapy. CYP3A4∗22 was shown to significantly influence the pharmacokinetics of several drugs, with currently being most thoroughly investigated tacrolimus, cyclosporine, and statins. Additional studies, focusing on toxicity and clinical outcome, are warranted to demonstrate clinical utility of CYP3A4∗22 genotype-based dosing.

scholarly journals Cytochrome P450 3A4 and 2D6-Mediated Metabolism of Leisure and Medicinal Teas

2014 ◽  
Vol 17 (3) ◽  
pp. 294 ◽  
Author(s):  
Teresa W Tam ◽  
Rui Liu ◽  
Ammar Saleem ◽  
John Thor Arnason ◽  
Anthony Krantis ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Camellia Sinensis ◽  
Plant Material ◽  
Tea Plant ◽  
Cytochrome P450 3A4 ◽  
Aqueous Extracts ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme

PURPOSE: Thirty-five commercially available Camellia sinensis (black and green) and herbal leisure teas and an assortment of Traditional Chinese medicinal teas were randomly selected and examined for their potential to inhibit the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4). The study was then extended to examine CYP2D6*1 and CYP2D6*10. METHODS: Microtiter fluorometric assays were utilized to examine the potential for the teas to inhibit CYP-mediated metabolism. Aqueous or alcoholic extracts of the dried tea plant material were examined. METHODS: Most of the black and green leisure teas generally inhibited CYP3A4 more than the Chinese medicinal teas. The medicinal Chinese teas were generally more inhibitory towards CYP3A4 compared to the CYP2D6 isozymes, and the aqueous extracts displayed more potency than the alcoholic extracts. CONCLUSIONS: Tea whether used for leisure or medicinal purposes has the potential to inhibit CYP3A4-mediated drug metabolism particularly black tea.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals CO Binding Kinetics of Human Cytochrome P450 3A4

1995 ◽  
Vol 270 (10) ◽  
pp. 5014-5018 ◽  
Author(s):  
Aditya P. Koley ◽  
Jeroen T. M. Buters ◽  
Richard C. Robinson ◽  
Allen Markowitz ◽  
Fred K. Friedman
Keyword(s):  
Cytochrome P450 ◽  
Binding Kinetics ◽  
Cytochrome P450 3A4 ◽  
Human Cytochrome ◽  
Kinetics Of

scholarly journals Estimation of polymorphisms in the drug-metabolizing enzyme, cytochrome P450 2C19 gene in six major ethnicities of Pakistan

Bioengineered ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 4442-4451
Author(s):  
Sagheer Ahmed ◽  
Saima Gul ◽  
Muhammad Akhlaq ◽  
Abrar Hussain ◽  
Sidrah Tariq Khan ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolizing Enzyme ◽  
Cytochrome P450 2C19 ◽  
Metabolizing Enzyme

scholarly journals Porcine foetal and neonatal CYP3A liver expression

2011 ◽  
Vol 1 (1) ◽  
pp. 1 ◽  
Author(s):  
Marie Louise Hiort Hermann ◽  
Mette Tingleff Skaanild
Keyword(s):  
Cytochrome P450 ◽  
Liver Microsomes ◽  
Cytochrome P450 3A4 ◽  
Chain Reaction ◽  
Hepatic Expression ◽  
Human Cytochrome ◽  
Foetal Liver ◽  
Polymerase Chain ◽  
Cyp3a Enzyme ◽  
Exogenous Substances

Human cytochrome P450 3A7 (CYP3A7) and cytochrome P450 3A4 (CYP3A4) are hepatic metabolising enzymes which participates in the biotransformation of endo- and exogenous substances in foetuses and neonates respectively. These CYP3A enzymes display an inverse relationship: CYP3A7 is the dominant enzyme in the foetal liver, whereas the expression of CYP3A4 is low. After parturition there is a shift in the expression, thus CYP3A7 is down regulated, while the level of CYP3A4 gradually increases and becomes the dominant metabolising CYP3A enzyme in the adult. The minipig is increasingly being used as a model for humans in biomedical studies, because of its many similarities with the human physiology and anatomy. The aim of this study was to examine whether, as in humans, a shift is seen in the hepatic expression of a CYP3A7- like enzyme to cytochrome P450 3A29 (CYP3A29) (an orthologue to the human CYP3A4) in minipigs. This was elucidated by examining the hepatic mRNA expression of CYP3A7 and CYP3A29 in 39 foetuses and newborn Göttingen minipigs using quantitative real time polymerase chain reaction (qPCR). Furthermore the immunochemical level of CYP3A7-LE and CYP3A29 was measured in liver microsomes using western blotting. The expression of CYP3A29 was approximately 9- fold greater in neonates compared to foetuses, and a similar difference was reflected on the immunochemical level. It was not possible to detect a significant level of foetal CYP3A7 mRNA, but immunoblotting showed a visible difference depending on age. This study demonstrates an increase in the expression of CYP3A29, the CYP3A4 orthologue in perinatal minipigs as in humans, which suggests that the minipig could be a good model when testing for human foetal toxicity towards CYP3A4 substrates.

scholarly journals Human Cytochrome P450 3A4 as a Biocatalyst: Effects of the Engineered Linker in Modulation of Coupling Efficiency in 3A4-BMR Chimeras

2017 ◽  
Vol 8 ◽  
Author(s):  
Danilo Degregorio ◽  
Serena D'Avino ◽  
Silvia Castrignanò ◽  
Giovanna Di Nardo ◽  
Sheila J. Sadeghi ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Coupling Efficiency ◽  
Cytochrome P450 3A4 ◽  
Human Cytochrome
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