PMID: 11901229Mar 20, 2002Paper

Cytochrome P450 3A conjugation to ubiquitin in a process distinct from classical ubiquitination pathway

Molecular Pharmacology
R C ZangarR T Okita

Abstract

We characterize a novel microsome system that forms high-molecular-mass (HMM) CYP3A, CYP2E1, and ubiquitin conjugates, but does not alter CYP4A or most other microsomal proteins. The formation of the HMM bands was observed in hepatic microsomes isolated from rats treated 1 week or more with high doses (50 mg/kg/day) of nicardipine, clotrimazole, or pregnenolone 16alpha-carbonitrile, but not microsomes from control, dexamethasone-, nifedipine-, or diltiazem-treated rats. Extensive washing of the microsomes to remove loosely attached proteins or cytosolic contaminants did not prevent the conjugation reaction. In contrast to prototypical ubiquitination pathways, this reaction did not require addition of ubiquitin, ATP, Mg(2+), or cytosol. Addition of cytosol did result in the degradation of the HMM CYP3A bands in a process that was not blocked by proteasome inhibitors. Immunoprecipitated CYP3A contained HMM ubiquitin. Even so, mass spectrometric analysis of tryptic peptides indicated that the HMM CYP3A was in molar excess to ubiquitin, suggesting that the formation of the HMM CYP3A may have resulted from conjugation to itself or a diffuse pool of ubiquitinated proteins already present in the microsomes. Addition of CYP3A substrate...Continue Reading

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Citations

Aug 2, 2003·Breast Cancer Research and Treatment·Susan M VarnumRichard C Zangar
Apr 12, 2005·Annual Review of Pharmacology and Toxicology·Maria Almira CorreiaEduardo Mundo-Paredes
Feb 3, 2007·Expert Opinion on Drug Metabolism & Toxicology·Maria Almira Correia, Mingxiang Liao
May 21, 2010·Drug Metabolism Reviews·Zdenek Dvorak, Peotr Pavek
Oct 4, 2011·Free Radical Biology & Medicine·Richard C ZangarNorman J Karin
Mar 19, 2003·Journal of Neurochemistry·Nobuyuki KuramotoYukio Yoneda
Jul 10, 2004·Biochemical Pharmacology·Richard C ZangarRobert S Chapkin
Jan 9, 2015·Analytical Chemistry·Didier FalconnetPatrick van den Bogaard
Mar 11, 2003·The Journal of Pharmacology and Experimental Therapeutics·Richard C ZangarDonna W Lee
Aug 21, 2020·Molecular Pharmacology·Choon-Myung LeeEdward T Morgan
Sep 10, 2008·The Biochemical Journal·Robert D FinnC Roland Wolf

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