TY - JOUR T1 - Selective and Potent Inhibition of Human CYP2C19 Activity by a Conformationally Targeted Antipeptide Antibody JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 715 LP - 717 VL - 28 IS - 7 AU - Timothy Schulz-Utermoehl AU - Richard J. Mountfield AU - Kjeld Madsen AU - Peer N. Jørgensen AU - Kristian T. Hansen Y1 - 2000/07/01 UR - http://dmd.aspetjournals.org/content/28/7/715.abstract N2 - A conformationally targeted anti-peptide antibody was produced by immunizing a rabbit with a cyclized peptide corresponding to a loop region of human CYP2C19 (residues 250–261). In an enzyme-linked immunosorbent assay, the antibody bound strongly to recombinant CYP2C19 and poorly to recombinant CYP2C8, CYP2C9, and CYP2C18. In immunoblotting studies, the antibody bound strongly to recombinant CYP2C19 and weakly to recombinant CYP2C8. No binding to recombinant CYP1A2, CYP2C9, CYP2C18, CYP2D6, CYP2E1, and CYP3A4 was detected. In immunoinhibition experiments, the anti-peptide antibody targeted against CYP2C19 potently inhibited (S)-mephenytoin 4′-hydroxylase activity of human hepatic microsomal fraction (>90%). It had no appreciable effect on ethoxyresorufinO-deethylase (CYP1A2), tolbutamide methyl-hydroxylase (CYP2C9), dextromethorphan O-demethylase (CYP2D6), 4-nitrophenol hydroxylase (CYP2E1), or testosterone 6β-hydroxylase (CYP3A4) activity of human hepatic microsomal fraction. However, large amounts of purified IgG fractions were able to inhibit up to 35% of paclitaxel 6α-hydroxylase (CYP2C8) activity. In conclusion, we have demonstrated that an anti-peptide antibody targeted against residues 250 to 261 of human CYP2C19 selectively and potently inhibited CYP2C19 activity of human hepatic microsomal fraction. The American Society for Pharmacology and Experimental Therapeutics ER -