Identification of the residue in human CYP3A4 that is covalently modified by bergamottin and the reactive intermediate that contributes to the grapefruit juice effect.

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Hsia-Lien LinPaul F Hollenberg

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 ...Continue Reading

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Citations

Jul 11, 2012·European Journal of Clinical Pharmacology·Sara K QuinneyStephen D Hall
Dec 22, 2012·Journal of Agricultural and Food Chemistry·Kyung MyungJan A Narciso
Feb 3, 2015·Drug Metabolism Reviews·Han Kiat HoEric Chun Yong Chan
Sep 5, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Dan LuJiang Zheng
Nov 14, 2012·The Journal of Pharmacy and Pharmacology·Nobutaka ArakiAkio Fujimura
Nov 1, 2007·Nutrition Journal·Jawad Kiani, Sardar Z Imam
Aug 9, 2016·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Zuzana E HaarhoffA David Rodrigues
Oct 1, 2016·Chemical Research in Toxicology·Arun TailorB Kevin Park
Mar 6, 2018·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Toshiyuki SakakiShinichi Ikushiro
Jul 28, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hsia-lien LinPaul F Hollenberg
Oct 3, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Amanda K BollesLaura Lowe Furge
Aug 27, 2019·Drug Metabolism Reviews·Bo Wen, Peter Gorycki
Aug 25, 2020·Toxicological Research·F Peter Guengerich
Apr 23, 2021·Proceedings of the National Academy of Sciences of the United States of America·Ryosuke MunakataKazufumi Yazaki
May 22, 2021·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Ying LiuJiang Zheng
Jun 26, 2021·Drug Metabolism and Pharmacokinetics·Kaori YasudaToshiyuki Sakaki
Jul 16, 2019·Chemical Research in Toxicology·Matthew K MatlockS Joshua Swamidass
Nov 18, 2021·Journal of Medicinal Food·Alexander BertuccioliGiordano Zonzini
Sep 4, 2021·Biomolecules & Therapeutics·F Peter Guengerich

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