Influence of different recombinant systems on the cooperativity exhibited by cytochrome P4503A4

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Z ZhangW Tang

Abstract

1. The in vitro cooperativity exhibited by cytochrome P450 (CYP) 3A4 is influenced by the nature of the recombinant system in which the phenomenon is studied. Diclofenac, piroxicam and R-warfarin were used as model substrates, and quinidine was the effector. 2. The 5-, 5'- and 10-hydroxylation of diclofenac, piroxicam and R-warfarin, respectively, were enhanced five- to sevenfold by quinidine in human liver microsomal incubations. Whereas these cooperative drug interactions were apparent in incubations with CYP3A4 expressed in human lymphoblast cells, similar phenomena were not observed with the enzyme expressed in insect cells. 3. Insect cell microsomes were treated with a detergent and CYP3A4 was solubilized into a buffer medium. In incubations with CYP3A4 'freed' from its host membrane, the 5-hydroxylation of diclofenac increased with increasing quinidine concentrations, reaching a maximal eightfold elevation relative to controls. The metabolism of piroxicam and warfarin was similarly enhanced by quinidine. 4. Kinetically, enhancement by quinidine of the 5-hydroxylation of diclofenac in incubations with solubilized CYP3A4 was characterized by increases in the rate of metabolism with little change in the substrate-binding aff...Continue Reading

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Citations

Aug 25, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Vikas KumarJan L Wahlstrom
Jun 27, 2009·Pharmacology & Therapeutics·Ilia G DenisovStephen G Sligar
Jan 22, 2008·Archives of Biochemistry and Biophysics·Dmitri R DavydovJames R Halpert
May 9, 2013·The Biochemical Journal·Dmitri R DavydovJames R Halpert
Feb 3, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Helinä KahmaJanne T Backman
Dec 24, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Diansong ZhouScott W Grimm
May 28, 2004·The Journal of Pharmacology and Experimental Therapeutics·Qing ChenWei Tang
Jul 23, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yury KapelyukhGordon C K Roberts
Sep 30, 2020·Cancer Chemotherapy and Pharmacology·Anand JoshiJan H Beumer
Nov 27, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mary Alexandra SchleiffGrover P Miller
Mar 24, 2021·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Helinä KahmaJanne T Backman

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