PMID: 9429232Jan 16, 1998Paper

A monoclonal antibody inhibitory to human P450 2D6: a paradigm for use in combinatorial determination of individual P450 role in specific drug tissue metabolism

Pharmacogenetics
H V GelboinT J Yang

Abstract

Human cytochrome P450 2D6 metabolizes more than 50 common drugs and is polymorphically expressed, with 5-10% of the population lacking expression caused by mutant genes. This may result in a defective and toxic response in deficient individuals treated with 2D6 drug substrates. Baculovirus-expressed 2D6 was used to immunize mice for hybridoma production and two clones yielded monoclonal antibodies, that were positive against 2D6 by ELISA and inhibited 2D6 catalysed metabolism of bufuralol, dextromethorphan and phenanthrene by more than 90%. The inhibitory activity was highly specific to 2D6 and the monoclonal antibodies did not bind to 11 other P450s, nor inhibit seven human P450s tested. Analysis of eight human liver microsome samples showed that their basal bufuralol 1'-hydroxylase activity varied from 6.7-83.5 pmol min-1 nmol-1 P450. The monoclonal antibody 512-1-8 inhibited 2D6-dependent bufuralol 1'-hydroxylase in these samples by 10-70% indicating a widely variable role for 2D6 in human liver bufuralol 1'-hydroxylase activity and a role for other P450s in bufuralol metabolism. Independent analysis of several recombinant human P450s showed that 2D6, 2C8, 2C9, 2C19 and 1A2 exhibited bufuralol 1'-hydroxylase activity with 2D...Continue Reading

Citations

Aug 11, 2000·Transplantation Proceedings·M KomaN Taniguchi
Nov 5, 1999·Trends in Pharmacological Sciences·H V GelboinT J Yang
Jan 18, 2003·Pharmacology & Toxicology·Mette T Skaanild, Christian Friis
May 9, 2002·Drug Metabolism Reviews·Slobodan Rendic
Oct 23, 2002·Critical Reviews in Toxicology·Janne HukkanenHannu Raunio
Feb 24, 2006·Journal of Clinical Pharmacology·Harry V Gelboin, Kristopher Krausz
Feb 8, 2014·Veterinary and Comparative Oncology·S Achanta, L K Maxwell
Apr 26, 2013·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Jie ChengFrank J Gonzalez
Dec 25, 2004·Drug Metabolism and Pharmacokinetics·Poh-Sing NgYoshihiko Funae
Feb 7, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Magang Shou, Anthony Y H Lu
Jan 23, 2003·The Journal of Pharmacology and Experimental Therapeutics·Ai-Ming YuFrank J Gonzalez
May 23, 2002·The Journal of Pharmacology and Experimental Therapeutics·Camille P GranvilFrank J Gonzalez
Mar 19, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Anthony Y H LuJiunn H Lin
Jul 22, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sharon L MiksysRachel F Tyndale
Nov 16, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Rae YuanShiew-Mei Huang
May 23, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Qin MeiMagang Shou
Nov 6, 2003·Biochemical Pharmacology·Connie CheungFrank J Gonzalez

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