ArticleDrug metabolism and disposition: the biological fate of chemicals2012
Identification of the residue in human CYP3A4 that is covalently modified by bergamottin and the reactive intermediate that contributes to the grapefruit juice effect.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 61 citations in OpenAlex.
- Rate of onset of inhibition of gut-wall and hepatic CYP3A by clarithromycin.European journal of clinical pharmacology · 2013Trial
- Bergamottin: a multitarget natural furanocoumarin with promising anticancer potential.Translational cancer research · 2026Review
- Molecular dynamics simulations elucidate the role of the F-F' loop in substrate entry into CYP3A4.Communications chemistry · 2026Article
- Network Analysis of the Herb-Drug Interactions of Citrus Herbs Inspired by the "Grapefruit Juice Effect".ACS omega · 2022Article
- Discovery and Visualization of Uncharacterized Drug-Protein Adducts Using Mass Spectrometry.Analytical chemistry · 2022Article
- Inhibition of Cytochrome P450 Enzymes by Drugs-Molecular Basis and Practical Applications.Biomolecules & therapeutics · 2022Review
- A Practical Perspective on the Use of Botanicals During the COVID-19 Pandemic: From Proven to Potential Interactions.Journal of medicinal food · 2022Review
- Parallel evolution of UbiA superfamily proteins into aromaticProceedings of the National Academy of Sciences of the United States of America · 2021Article
- A history of the roles of cytochrome P450 enzymes in the toxicity of drugs.Toxicological research · 2021Review
- Article
- Convergent evolution of the UbiA prenyltransferase family underlies the independent acquisition of furanocoumarins in plants.The New phytologist · 2020Article
- Structural Perspectives of the CYP3A Family and Their Small Molecule Modulators in Drug Metabolism.Liver research (Beijing, China) · 2019Article
- Structural Insights into the Interaction of Cytochrome P450 3A4 with Suicide Substrates: Mibefradil, Azamulin and 6',7'-Dihydroxybergamottin.International journal of molecular sciences · 2019Article
- A Time-Embedding Network Models the Ontogeny of 23 Hepatic Drug Metabolizing Enzymes.Chemical research in toxicology · 2019Article
- Coordination Mechanism and Bio-Evidence: Reactive γ-Ketoenal Intermediated Hepatotoxicity of Psoralen and Isopsoralen Based on Computer Approach and Bioassay.Molecules (Basel, Switzerland) · 2017Article
- Functioning of drug-metabolizing microsomal cytochrome P450s: In silico probing of proteins suggests that the distal heme 'active site' pocket plays a relatively 'passive role' in some enzyme-substrate interactions.In silico pharmacology · 2016Article
- A Ligand-Based Drug Design. Discovery of 4-Trifluoromethyl-7,8-pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2.Journal of medicinal chemistry · 2015Article
- Mechanism-based inactivation of CYP450 enzymes: a case study of lapatinib.Drug metabolism reviews · 2015Review
- Article
- Mechanism-based inactivation of human cytochrome P450 3A4 by two piperazine-containing compounds.Drug metabolism and disposition: the biological fate of chemicals · 2014Article
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3 authors at 1 institution in 1 country.
Funding
Abstract
Previous studies have demonstrated that bergamottin (BG), a component of grapefruit juice, is a mechanism-based inactivator of CYP3A4 and contributes, in part, to the grapefruit juice-drug interaction. Although the covalent binding of [(14)C]BG to the CYP3A4 apoprotein has been demonstrated by SDS-polyacrylamide gel electrophoresis, the identity of the modified amino acid residue and the reactive intermediate species of BG responsible for the inactivation have not been reported. In the present study, we show that inactivation of CYP3A4 by BG results in formation of a modified apoprotein-3A4 and a GSH conjugate, both exhibiting mass increases of 388 Da, which corresponds to the mass of 6',7'-dihydroxybergamottin (DHBG), a metabolite of BG, plus one oxygen atom. To identify the adducted residue, BG-inactivated 3A4 was digested with trypsin, and the digests were then analyzed by liquid chromatography-tandem mass spectrometry (MS/MS). A mass shift of 388 Da was used for the SEQUEST database search, which revealed a mass increase of 388 Da for the peptide with the sequence (272)LQLMIDSQNSK(282), and MS/MS analysis of the adducted peptide demonstrated that Gln273 is the residue modified. Mutagenesis studies showed that the Gln273 to Val mutant was resistant to inactivation by BG and DHBG and did not generate two of the major metabolites of BG formed by 3A4 wild type. In conclusion, we have determined that the reactive intermediate, oxygenated DHBG, covalently binds to Gln273 and thereby contributes to the mechanism-based inactivation of CYP3A4 by BG.
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