Mechanism-based inactivation of cytochrome P450 3A4 by L-754,394

L K LightningW F Trager


Mechanism-based inactivation of human liver P450 3A4 by L-754,394, a Merck compound synthesized as a potential HIV protease inhibitor, was investigated using recombinant P450 3A4. Enzyme inactivation was characterized by a small partition ratio (3.4 or 4.3 +/- 0.4), i.e., the total number of metabolic events undergone by the inhibitor divided by the number of enzyme inactivating events, lack of reversibility upon extensive dialysis, no decrease in the characteristic 450-nm species relative to control, and covalent modification of the apoprotein. The major and minor products formed during the inactivation of P450 3A4 were the monohydroxylated and the dihydrodiol metabolites of L-754,394, respectively. L-754,394 that had been adducted to P450 3A4 was hydrolyzed under the conditions used for SDS-PAGE, Ni(2+) affinity chromatography, and proteolytic digestion. In addition, the modification was not stable to the acidic conditions of HPLC separation and CNBr digestion. The labile nature of the peptide adduct and the nonstoichiometric binding of the inactivating species to P450 3A4 precluded the direct identification of a covalently modified amino acid residue or the peptide to which it was attached. However, Tricine SDS-PAGE in combi...Continue Reading


Nov 19, 2013·Inorganic Chemistry·Nikhil TaxakPrasad V Bharatam
Oct 16, 2012·Chemical Research in Toxicology·Lisa A Peterson
Mar 25, 2008·Therapeutics and Clinical Risk Management·Shu-Feng ZhouMin Huang
Mar 15, 2005·Clinical Pharmacokinetics·Shu-Feng ZhouHoward L McLeod
May 9, 2002·Drug Metabolism Reviews·Slobodan Rendic
Jul 7, 2007·Critical Reviews in Toxicology·Y Masubuchi, T Horie
Mar 8, 2005·Drug Metabolism Reviews·Shufeng ZhouYu-Zong Chen
Nov 17, 2009·Bioorganic & Medicinal Chemistry Letters·Derek C MartynJon Clardy
Sep 9, 2006·Archives of Biochemistry and Biophysics·Bo WenSidney D Nelson
Nov 18, 2005·Archives of Biochemistry and Biophysics·Bo WenSidney D Nelson
Jun 21, 2006·The Journal of Pharmacology and Experimental Therapeutics·U M KentP F Hollenberg
May 18, 2005·Journal of Enzyme Inhibition and Medicinal Chemistry·Petr HodekMarie Stiborová
Aug 9, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kishore K KhanJ R Halpert
Oct 3, 2014·Molecular Pharmacology·Brooke M RockKent L Kunze
Apr 27, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mohamad Shebley, P F Hollenberg
Nov 22, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·E RowM S Lennard
Mar 27, 2021·Chemical Research in Toxicology·M Saeed MirzaeiSaber Mirzaei
Mar 26, 2009·Chemical Research in Toxicology·Manuel Tzouros, Axel Pähler
Sep 9, 2004·Chemical Reviews·Bernard MeunierSason Shaik

Related Concepts

CYP3A protein, human
Plasma Membrane
High Pressure Liquid Chromatography Procedure
In Silico
Cyanogen Bromide
Cytochrome P-450 Oxygenase
Physical Dialysis
Alkalescens-Dispar Group

Trending Feeds


Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Lipidomics & Rhinovirus Infection

Lipidomics can be used to examine the lipid species involved with pathogenic conditions, such as viral associated inflammation. Discovered the latest research on Lipidomics & Rhinovirus Infection.

Spatio-Temporal Regulation of DNA Repair

DNA repair is a complex process regulated by several different classes of enzymes, including ligases, endonucleases, and polymerases. This feed focuses on the spatial and temporal regulation that accompanies DNA damage signaling and repair enzymes and processes.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Torsion Dystonia

Torsion dystonia is a movement disorder characterized by loss of control of voluntary movements appearing as sustained muscle contractions and/or abnormal postures. Here is the latest research.

Archaeal RNA Polymerase

Archaeal RNA polymerases are most similar to eukaryotic RNA polymerase II but require the support of only two archaeal general transcription factors, TBP (TATA-box binding protein) and TFB (archaeal homologue of the eukaryotic general transcription factor TFIIB) to initiate basal transcription. Here is the latest research on archaeal RNA polymerases.

Alzheimer's Disease: MS4A

Variants within the membrane-spanning 4-domains subfamily A (MS4A) gene cluster have recently been implicated in Alzheimer's disease in genome-wide association studies. Here is the latest research on Alzheimer's disease and MS4A.

Central Pontine Myelinolysis

Central Pontine Myelinolysis is a neurologic disorder caused most frequently by rapid correction of hyponatremia and is characterized by demyelination that affects the central portion of the base of the pons. Here is the latest research on this disease.