Effect of P450 oxidoreductase variants on the metabolism of model substrates mediated by CYP2C9.1, CYP2C9.2, and CYP2C9.3

Pharmacogenetics and Genomics
Murali SubramanianTimothy S Tracy

Abstract

CYP2C9 is a microsomal cytochrome P450 that receives electrons from P450 oxidoreductase (POR) to metabolize about 15% of clinically used drugs. Similar to many P450 enzymes, CYP2C9 is polymorphic, with the hypomorphic *2 and *3 variants accounting for about 20% of White alleles. POR is also polymorphic, with the amino acid sequence variant A503V accounting for 19-37% of alleles in different populations. We aimed to understand how polymorphisms in these two interacting proteins might affect drug metabolism. We assayed the activities of CYP2C9.1, CYP2C9.2, and CYP2C9.3 to metabolize diclofenac, flurbiprofen, and tolbutamide using a wild type or one of four POR variants (Q153R, A287P, R457H, and A503V). Human CYP2C9 and POR variants were expressed in bacteria, purified, and reconstituted in vitro and the Michaelis constant and maximum velocity were measured with each CYP2C9/POR combination and each substrate. With wild-type POR, the CYP2C9 activities were CYP2C9.1>CYP2C9.2>CYP2C9.3 with all three substrates. Both the common A503V polymorphism and the rare Q153R variant showed modest increases in activity with all three CYP2C9 isoforms and all three substrates. This is in contrast to previous studies in which A503V showed a modest ...Continue Reading

References

Aug 5, 1997·Proceedings of the National Academy of Sciences of the United States of America·M WangJ J Kim
Jun 27, 1998·The Journal of Biological Chemistry·A BridgesLucy Waskell
Mar 20, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Timothy S TracyLeslie J Dickmann
Apr 3, 2002·JAMA : the Journal of the American Medical Association·Mitchell K HigashiAllan E Rettie
Sep 18, 2002·Clinical Pharmacology and Therapeutics·Mikko NiemiKari T Kivistö
Mar 21, 2006·Archives of Biochemistry and Biophysics·Charles W LocusonTimothy S Tracy
Apr 6, 2006·The AAPS Journal·F Peter Guengerich
Apr 6, 2006·The AAPS Journal·Michael P Holt, Cynthia Ju
Sep 12, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Vikas KumarTimothy S Tracy
Jun 28, 2007·Molecular Endocrinology·Amit V PandeyChrista E Flück
Dec 7, 2007·Chemical Research in Toxicology·F Peter Guengerich
Jan 31, 2008·Proceedings of the National Academy of Sciences of the United States of America·Ningwu HuangWalter L Miller
Apr 10, 2008·The Journal of Clinical Endocrinology and Metabolism·Larissa G GomesWalter L Miller
Jun 14, 2008·Pharmacogenetics and Genomics·Vishal AgrawalWalter L Miller
Jul 16, 2008·Analytical and Bioanalytical Chemistry·Emre M Isin, F Peter Guengerich
Jun 12, 2009·Drug Metabolism Reviews·Shu-Feng ZhouBalram Chowbay
Mar 2, 2010·Molecular and Cellular Endocrinology·Catherine NicoloAmit V Pandey
Aug 11, 2010·Pharmacogenetics and Genomics·Vishal AgrawalWalter L Miller
Sep 17, 2010·European Journal of Endocrinology·Dorota Tomalik-ScharteWiebke Arlt
Oct 14, 2010·Pharmacogenetics and Genomics·Duanpen SandeeWalter L Miller
May 13, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Xiuling ZhangLaurence Kaminsky
Aug 3, 2011·Proceedings of the National Academy of Sciences of the United States of America·Chuanwu XiaJung-Ja P Kim

Citations

Jun 6, 2013·Applied Biochemistry and Biotechnology·Ina NeunzigMatthias Bureik
Jan 29, 2013·Pharmacology & Therapeutics·Amit V Pandey, Christa E Flück
Aug 19, 2014·Chemical Research in Toxicology·Sylvie E Kandel, Jed N Lampe
Jun 3, 2014·Pharmacology & Therapeutics·Payman ShahabiSophie Visvikis-Siest
Dec 4, 2014·Basic & Clinical Pharmacology & Toxicology·Da-Peng DaiJian-Ping Cai
Jun 13, 2015·Pharmacogenomics·Rebecca A PulkDeKAF Investigators
Feb 26, 2015·Pharmacogenomics·Mária TomkováPavel Martásek
Dec 30, 2014·European Journal of Drug Metabolism and Pharmacokinetics·Kenji OgataKeiichi Kawai
Oct 27, 2017·Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology·Tianran SongHaixiang Sun
Nov 10, 2017·PloS One·Ibrahim El-SerafiMoustapha Hassan
Oct 11, 2012·Pharmacogenetics and Genomics·Lei HuLan Fan
Nov 3, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Teresa CabaleiroFrancisco Abad-Santos
Nov 12, 2019·Diabetic Medicine : a Journal of the British Diabetic Association·L ChenJ C Florez
Nov 1, 2019·The Journal of Steroid Biochemistry and Molecular Biology·Shaheena ParweenAmit V Pandey
Apr 14, 2016·The Journal of Steroid Biochemistry and Molecular Biology·Fabian Z BurkhardAmit V Pandey

Related Concepts

CYP2C9 protein, human
Xenobiotic Monooxygenases
Catalysis
Diclonate P
ratio-Flurbiprofen
NADPH-Ferrihemoprotein Reductase
Genetic Polymorphism
Proteins, Recombinant DNA
Tolbutamid R.A.N.
Cytochrome p450 CYP2C9 enzyme

Trending Feeds

COVID-19

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.

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.

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.

Generating Insulin-Secreting Cells

Reprogramming cells or using induced pluripotent stem cells to generate insulin-secreting cells has significant therapeutic implications for diabetics. Here is the latest research on generation of insulin-secreting cells.

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.

Epigenome Editing

Epigenome editing is the directed modification of epigenetic marks on chromatin at specified loci. This tool has many applications in research as well as in the clinic. Find the latest research on epigenome editing here.