Identifying a selective substrate and inhibitor pair for the evaluation of CYP2J2 activity.

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Caroline A LeeRheem A Totah

Abstract

CYP2J2, an arachidonic acid epoxygenase, is recognized for its role in the first-pass metabolism of astemizole and ebastine. To fully assess the role of CYP2J2 in drug metabolism, a selective substrate and potent specific chemical inhibitor are essential. In this study, we report amiodarone 4-hydoxylation as a specific CYP2J2-catalyzed reaction with no CYP3A4, or other drug-metabolizing enzyme, involvement. Amiodarone 4-hydroxylation enabled the determination of liver relative activity factor and intersystem extrapolation factor for CYP2J2. Amiodarone 4-hydroxylation correlated with astemizole O-demethylation but not with CYP2J2 protein content in a sample of human liver microsomes. To identify a specific CYP2J2 inhibitor, 138 drugs were screened using terfenadine and astemizole as probe substrates with recombinant CYP2J2. Forty-two drugs inhibited CYP2J2 activity by ≥50% at 30 μM, but inhibition was substrate-dependent. Of these, danazol was a potent inhibitor of both hydroxylation of terfenadine (IC(50) = 77 nM) and O-demethylation of astemizole (K(i) = 20 nM), and inhibition was mostly competitive. Danazol inhibited CYP2C9, CYP2C8, and CYP2D6 with IC(50) values of 1.44, 1.95, and 2.74 μM, respectively. Amiodarone or astemizo...Continue Reading

References

Jun 5, 2002·Current Opinion in Lipidology·Deanna L Kroetz, Darryl C Zeldin
Oct 19, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Shigeki MatsumotoYasushi Yamazoe
Nov 26, 2003·Progress in Lipid Research·Arthur A SpectorNeal L Weintraub
Mar 23, 2004·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Ahmed E EnayetallahDavid F Grant
Feb 10, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mary F PaineDarryl C Zeldin
Feb 24, 2006·Bioorganic & Medicinal Chemistry Letters·Pierre LafiteDaniel Mansuy
Jul 27, 2006·The Journal of Pharmacology and Experimental Therapeutics·Andrea GaedigkJ Steven Leeder
Dec 13, 2006·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·H YamazakiM Shimizu
May 2, 2007·Archives of Biochemistry and Biophysics·Pierre LafiteDaniel Mansuy
Mar 18, 2009·The Journal of Pharmacology and Experimental Therapeutics·Chen ChenDao Wen Wang
Nov 20, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Caroline A LeeRheem A Totah
Oct 30, 2010·The Journal of Pharmacology and Experimental Therapeutics·Chen ChenDao Wen Wang
Nov 26, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Gregory S WalkerAmy Freund
Mar 15, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Pan DengDafang Zhong

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Citations

May 14, 2014·Annual Review of Nutrition·David Bishop-BaileyCaroline Wheeler-Jones
Jun 29, 2014·Biochemical Pharmacology·Rüdiger KasperaRheem A Totah
Apr 22, 2014·Journal of Pharmaceutical and Biomedical Analysis·Dany SpaggiariSerge Rudaz
Mar 12, 2013·Prostaglandins & Other Lipid Mediators·Ara AskariDavid Bishop-Bailey
Jan 2, 2016·Pharmacological Reviews·Janne T BackmanPertti J Neuvonen
Feb 27, 2016·Molecular Pharmaceutics·Ahmed A El-Sherbeni, Ayman O S El-Kadi
May 11, 2013·Protein Science : a Publication of the Protein Society·Daniel R McDougleAditi Das
May 3, 2014·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Boram LeeKwang-Hyeon Liu
Jul 6, 2014·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Jian LuXin Wang
Jan 7, 2015·Pharmacological Reports : PR·Annan Sudarsan Arun KumarChandrasekaran Adithan
Mar 24, 2016·The Journal of Pharmacology and Experimental Therapeutics·Vyvyca J WalkerPaul F Hollenberg
Jun 11, 2016·Drug Metabolism Reviews·Michael Murray
Nov 1, 2016·Journal of Molecular Modeling·G ProiettiI Nobeli
Nov 8, 2016·Drug Metabolism Reviews·Ahmed A El-Sherbeni, Ayman O S El-Kadi
Sep 16, 2018·Journal of Clinical Pharmacy and Therapeutics·Rashmi R Shah, Peter D Stonier
Apr 1, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hsia-Lien LinPaul F Hollenberg
May 4, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Nguyen Minh PhucKwang-Hyeon Liu
Jul 13, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hsia-Lien LinPaul F Hollenberg
Jan 19, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Eric A EvangelistaRheem A Totah
Jan 6, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Eleanor Jing Yi CheongEric Chun Yong Chan
Sep 11, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ping YiJason Johnson
Oct 4, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Shuang RenLi Chen
Jun 7, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Eunyoung LeeKwang-Hyeon Liu
Sep 12, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Eric A EvangelistaRheem A Totah
Jul 9, 2017·Proceedings of the National Academy of Sciences of the United States of America·Daniel R McDougleAditi Das
Sep 12, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Eleanor Jing Yi CheongEric Chun Yong Chan
May 6, 2014·Toxicological Research·Hyoung-Goo ParkDonghak Kim
Jul 4, 2018·International Journal of Molecular Sciences·Theresa AliwargaRheem A Totah
Jul 18, 2018·International Journal of Molecular Sciences·Pierre LafiteDaniel Mansuy
May 2, 2018·Free Radical Biology & Medicine·Ji Won ParkEdward T Morgan
Jun 15, 2020·Pharmacology & Therapeutics·Aditi DasHannah C Huff
May 28, 2021·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Jacqueline Wen Hui LeowEric Chun Yong Chan

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