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
References
May 15, 1989·Biochemical Pharmacology·D C MaysN Gerber
Jul 1, 1995·Clinical Pharmacology and Therapeutics·H H KupferschmidtS Krähenbühl
May 1, 1995·Clinical Pharmacology and Therapeutics·M P DucharmeD J Edwards
Jun 1, 1993·Biological Mass Spectrometry·T A Baillie, M R Davis
Jul 1, 1993·Chemical Research in Toxicology·E S RobertsP F Hollenberg
Apr 1, 1996·Clinical Pharmacology and Therapeutics·R E BentonR L Woosley
Sep 1, 1996·Chemical Research in Toxicology·Y Sahali-SahlyT A Baillie
May 5, 1998·Chemical Research in Toxicology·K HeP F Hollenberg
Jul 17, 1998·Biochemistry·L L Koenigs, W F Trager
Sep 2, 1998·British Journal of Clinical Pharmacology·D G BaileyJ D Spence
Sep 28, 1998·Biochemistry·L L Koenigs, W F Trager
Apr 12, 2000·Biochemistry·L K LightningW F Trager
Jun 22, 2000·Archives of Biochemistry and Biophysics·W TassaneeyakulY Yamazoe
Jul 25, 2000·British Journal of Pharmacology·A OhnishiY Sawada
Dec 5, 2000·Clinical Pharmacology and Therapeutics·D G BaileyJ R Bend
Aug 9, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yuan Hua WenVsevolod E Kostrubsky
Oct 31, 2002·CMAJ : Canadian Medical Association Journal = Journal De L'Association Medicale Canadienne·J David Spence
Jun 5, 2004·Clinical Pharmacology and Therapeutics·Shefali M KakarPaul B Watkins
Jul 23, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mary F PainePaul B Watkins
Oct 19, 2004·Chemical Research in Toxicology·Kevin P BatemanDeborah A Nicoll-Griffith
Dec 14, 2004·Clinical Pharmacology and Therapeutics·Theunis C GoosenH Paul Dijkstra
Dec 21, 2004·The Journal of Pharmacology and Experimental Therapeutics·Hsia-lien LinPaul F Hollenberg
May 11, 2006·The American Journal of Clinical Nutrition·Mary F PainePaul B Watkins
Jun 21, 2006·The Journal of Pharmacology and Experimental Therapeutics·Ute M KentPaul F Hollenberg
May 15, 2007·Chemical Research in Toxicology·Brian R BaerDan A Rock
Sep 18, 2007·Chemical Research in Toxicology·Hideo YukinagaKen-Ichi Sudo
Nov 16, 2007·Chemical Research in Toxicology·Josh T PearsonDan A Rock
Jan 27, 2009·The Journal of Pharmacology and Experimental Therapeutics·Hsia-lien LinPaul F Hollenberg
Sep 2, 2009·Molecular Pharmacology·Haoming ZhangPaul F Hollenberg
Mar 5, 2010·The Journal of Pharmacology and Experimental Therapeutics·Hsia-lien LinPaul F Hollenberg
Sep 15, 2010·Archives of Biochemistry and Biophysics·Haoming ZhangPaul F Hollenberg
Sep 21, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hsia-lien LinPaul F Hollenberg
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
Oct 15, 2013·Journal of Agricultural and Food Chemistry·Audray DugrandFrédéric Bourgaud
Feb 3, 2015·Drug Metabolism Reviews·Han Kiat HoEric Chun Yong Chan
Feb 20, 2016·In Silico Pharmacology·Avanthika VenkatachalamKelath Murali Manoj
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
Dec 5, 2014·Food Science & Nutrition·Xue Fen KoeMei Lan Tan
Jul 30, 2015·Journal of Medicinal Chemistry·Jiawang LiuMaryam Foroozesh
Nov 1, 2007·Nutrition Journal·Jawad Kiani, Sardar Z Imam
Sep 3, 2008·Chemico-biological Interactions·Pim W J de WaardTheo M C M de Kok
Aug 9, 2016·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Zuzana E HaarhoffA David Rodrigues
Aug 12, 2014·Chemical Research in Toxicology·Yanou YangYue-Zhong Shu
Sep 12, 2014·Chemical Research in Toxicology·Annika ThorsellUlrik Jurva
Oct 1, 2016·Chemical Research in Toxicology·Arun TailorB Kevin Park
Nov 13, 2015·PloS One·Audray Dugrand-JudekFrédéric Bourgaud
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
Feb 7, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hongbin YuZhaopie Zeng
Aug 4, 2012·Molecular Pharmacology·Brooke M VandenBrinkDan A Rock
Oct 24, 2019·The New Phytologist·Ryosuke MunakataKazufumi Yazaki
Sep 5, 2019·International Journal of Molecular Sciences·Irina F Sevrioukova
Aug 27, 2019·Drug Metabolism Reviews·Bo Wen, Peter Gorycki
Apr 9, 2020·Antioxidants·Mariarosaria LeporiniRosa Tundis
Aug 25, 2020·Toxicological Research·F Peter Guengerich
Sep 4, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yue HaiXin He
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