Pharmacogenomics of human liver cytochrome P450 oxidoreductase: multifactorial analysis and impact on microsomal drug oxidation

Pharmacogenomics
Ana M GomesUlrich M Zanger

Abstract

NADPH:CYP oxidoreductase (POR) is an essential component of several enzyme systems, including the microsomal CYP monooxygenases. We investigated genetic and nongenetic POR variability and its impact on drug-oxidation activities in human liver microsomes. POR mRNA, protein and activity, as well as ten major drug-oxidation activities, were measured in the microsomes of 150 Caucasian surgical liver samples. Matrix-assisted laser desorption/ionisation-time of flight mass spectrometric assays were established to determine the frequency of 46 selected POR SNPs. Multivariate log-linear regression models, including main effects and two-way interaction terms, and analyses of variance were used to identify statistically significant relationships. POR phenotypes were less variable within the study population as compared with CYP phenotypes. Intronic SNPs g.18557G>A (intron 2), g.25676C>T (intron 3) and g.30986 G>A (intron 10) were associated with various drug-oxidation activities. The common allele POR*28 (A503V) was not associated with any activity or expression changes. Haplotype analysis identified two novel composite alleles POR*36 (P228L plus A503V) and POR*37 (A503V plus V631I). Models that integrate POR and microsomal CYP function ...Continue Reading

References

Mar 1, 1992·Archives of Biochemistry and Biophysics·S TamuraF J Gonzalez
Apr 1, 1992·Archives of Biochemistry and Biophysics·E A ShephardI R Phillips
Nov 1, 1990·Chemical Research in Toxicology·R PeterC S Yang
Oct 1, 1990·Clinical Pharmacology and Therapeutics·D L SchmuckerP Kremers
Oct 23, 1974·Biochemical and Biophysical Research Communications·J L Vermilion, M J Coon
Dec 1, 1995·Naunyn-Schmiedeberg's Archives of Pharmacology·D BusseMichel Eichelbaum
Aug 5, 1997·Proceedings of the National Academy of Sciences of the United States of America·M WangJ J Kim
Aug 2, 2001·Human Genetics·J T den Dunnen, S E Antonarakis
Jan 24, 2002·The Journal of Pharmacology and Experimental Therapeutics·Xue-Qing LiCollen M Masimirembwa
May 3, 2003·Pharmacology & Therapeutics·Wayne L Backes, Rusty W Kelley
Jun 13, 2003·Proceedings of the National Academy of Sciences of the United States of America·Chunming Ding, Charles R Cantor
Sep 27, 2003·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Renzo WolboldUlrich M Zanger
Oct 18, 2003·The Journal of Pharmacology and Experimental Therapeutics·Tanja RichterUlrich M Zanger
Oct 24, 2003·American Journal of Human Genetics·Matthew Stephens, Peter Donnelly
Apr 23, 2004·Pharmacogenomics·David F V Lewis
Jul 9, 2004·Drug Metabolism Reviews·F Peter Guengerich
Jul 25, 2006·Expert Opinion on Drug Metabolism & Toxicology·James J CaliDavid Liu
Jun 28, 2007·Molecular Endocrinology·Amit V PandeyChrista E Flück
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
Apr 25, 2008·Expert Opinion on Drug Metabolism & Toxicology·Steven N Hart, Xiao-Bo Zhong
May 22, 2008·Endocrine Development·Christa E FlückWalter L Miller
Jun 14, 2008·Pharmacogenetics and Genomics·Vishal AgrawalWalter L Miller
Aug 13, 2008·Analytical and Bioanalytical Chemistry·Ulrich M ZangerMatthias Schwab
Oct 22, 2008·Molecular and Cellular Endocrinology·Walter L MillerKathleen M Giacomini

Citations

Oct 26, 2012·European Journal of Clinical Pharmacology·Jing-Jing ZhangLi-Yan Miao
Oct 11, 2012·Pharmacogenetics and Genomics·Lei HuLan Fan
Jan 18, 2013·Pharmacogenetics and Genomics·Laure ElensRon H N Van Schaik
Nov 4, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Christopher C MarohnicMichel Kranendonk
May 13, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Xiuling ZhangLaurence S Kaminsky
Jan 19, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Daniela MoutinhoMichel Kranendonk
Nov 19, 2010·Drug Metabolism and Pharmacokinetics·Yoshiro SaitoTomohide Tamura
Jan 18, 2013·International Journal of Molecular Sciences·Songklod SarapusitPornpimol Rongnoparut
Sep 17, 2010·European Journal of Endocrinology·Dorota Tomalik-ScharteWiebke Arlt
Sep 26, 2013·Therapeutic Drug Monitoring·Laure ElensRon H N Van Schaik
Mar 15, 2011·Expert Opinion on Drug Metabolism & Toxicology·Dmitri R Davydov
Jan 20, 2016·Archives of Toxicology·Lucia PelléStefano Landi
Jan 29, 2013·Pharmacology & Therapeutics·Amit V Pandey, Christa E Flück
Sep 18, 2012·Archives of Biochemistry and Biophysics·Takashi IyanagiJung-Ja P Kim
Jul 12, 2011·Archives of Biochemistry and Biophysics·Christopher C MarohnicBettie Sue Siler Masters
Aug 25, 2010·Biochemical and Biophysical Research Communications·Amit V PandeyPrimus E Mullis
Mar 2, 2010·Molecular and Cellular Endocrinology·Catherine NicoloAmit V Pandey
Aug 17, 2011·Biochemical and Biophysical Research Communications·Christa E FlückAmit V Pandey
Jun 13, 2015·Pharmacogenomics·Rebecca A PulkDeKAF Investigators
Feb 26, 2015·Pharmacogenomics·Mária TomkováPavel Martásek
Oct 2, 2009·Clinical Pharmacology and Therapeutics·S RiedmaierUlrich M Zanger
Jun 25, 2016·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Na GaoHai-Ling Qiao
Jun 9, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hai-Feng ZhangHai-Ling Qiao

Methods Mentioned

BETA
genotyping
PCRs

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