title: Metabolism of BYZX in human liver microsomes and cytosol: identification of the metabolites and metabolic pathways of BYZX.
abstract: BYZX, [(E)-2-(4-((diethylamino)methyl)benzylidene)-5,6-dimethoxy-2,3-dihydroinden-one], belongs to a series of novel acetylcholinesterase inhibitors and has been synthesized as a new chemical entity for the treatment of Alzheimer's disease symptoms. When incubated with human liver microsomes (HLMs), BYZX was rapidly transformed into its metabolites M1, M2, and M3. The chemical structures of these metabolites were identified using liquid chromatography tandem mass spectrometry and nuclear magnetic resonance, which indicated that M1 was an N-desethylated and C = C hydrogenation metabolite of BYZX. M2 and M3 were 2 precursor metabolites, which resulted from the hydrogenation and desethylation of BYZX, respectively. Further studies with chemical inhibitors and human recombinant cytochrome P450s (CYPs), and correlation studies were performed. The results indicated that the N-desethylation of BYZX and M2 was mediated by CYP3A4 and CYP2C8. The reduced form of β-nicotinamide adenine dinucleotide 2'-phosphate was involved in the hydrogenation of BYZX and M3, and this reaction occurred in the HLMs and in the human liver cytosol. The hydrogenation reaction was not inhibited by any chemical inhibitors of CYPs, but it was significantly inhibited by some substrates of α,β-ketoalkene C = C reductases and their inhibitors such as benzylideneacetone, dicoumarol, and indomethacin. Our results suggest that α,β-ketoalkene C = C reductases may play a role in the hydrogenation reaction, but this issue requires further clarification.
authors.affiliation: Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Lushan
authors.initials: L
authors.lastname: Yu
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Sheng
authors.forename: Yongzhou
authors.initials: Y
authors.lastname: Hu
authors.forename: Su
authors.initials: S
authors.lastname: Zeng
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002853:Chromatography, Liquid; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D006859:Hydrogen / Q000737:chemistry; D007192:Indenes / Q000494:pharmacology*; D007213:Indomethacin / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways; D008862:Microsomes, Liver / Q000378:metabolism*
chemical_list: C543150:2-(4-((dimethylamino)methyl)benzylidene)-5,6-dimethoxy-2,3-dihydroinden-1-one; D001597:Benzylidene Compounds; D004791:Enzyme Inhibitors; D007192:Indenes; D006859:Hydrogen; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007213:Indomethacin
references.citation: Dermatology. 1996;193(3):177-84
references.pmid: 8944337
references.citation: Drug Metab Dispos. 2002 Apr;30(4):414-20
references.pmid: 11901095
references.citation: Xenobiotica. 1998 Dec;28(12):1167-202
references.pmid: 9890158
references.citation: Drug Metab Dispos. 1999 Jul;27(7):763-6
references.pmid: 10383917
references.citation: Clin Cancer Res. 2005 Jun 15;11(12):4365-71
references.pmid: 15958619
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Oct 1;857(2):266-74
references.pmid: 17709305
references.citation: Nat Rev Drug Discov. 2005 May;4(5):410-20
references.pmid: 15864270
references.citation: Drug Discov Today. 2004 Jun 1;9(11):478-84
references.pmid: 15149623
references.citation: Int J Clin Pharmacol Ther. 1998 Dec;36(12):642-51
references.pmid: 9877001
references.citation: J Pharmacol Exp Ther. 1999 Feb;288(2):679-84
references.pmid: 9918575
references.citation: Curr Drug Metab. 2003 Oct;4(5):341-6
references.pmid: 14529366
references.citation: Biochemistry. 1998 Mar 24;37(12):4137-47
references.pmid: 9521735
references.citation: Bioorg Med Chem Lett. 2005 Sep 1;15(17):3834-7
references.pmid: 15993600
references.citation: Lancet. 2000 Nov 4;356(9241):1587-91
references.pmid: 11075787
references.citation: Drug Metab Dispos. 2005 Feb;33(2):262-70
references.pmid: 15547048
references.citation: Clin Pharmacol Ther. 1996 Dec;60(6):601-7
references.pmid: 8988062
references.citation: Drug Metab Dispos. 2011 May;39(5):927-32
references.pmid: 21270106
references.citation: Drug Metab Dispos. 2003 Jul;31(7):815-32
references.pmid: 12814957
references.citation: PLoS One. 2012;7(6):e38495
references.pmid: 22719896
references.citation: Xenobiotica. 2008 Mar;38(3):249-63
references.pmid: 18274955
references.citation: Drug Metab Dispos. 2003 Sep;31(9):1108-16
references.pmid: 12920166
references.citation: Biochem Mol Biol Int. 1996 Aug;39(6):1157-65
references.pmid: 8876969
references.citation: J Clin Invest. 1993 Aug;92(2):903-10
references.pmid: 7688765
references.citation: Eur J Pharmacol. 2009 Jun 24;613(1-3):1-9
references.pmid: 19345205
references.citation: Eur J Med Chem. 2009 Jan;44(1):7-17
references.pmid: 18436348
references.citation: Drug Metab Dispos. 2005 Aug;33(8):1115-23
references.pmid: 15863696
references.citation: Biochem J. 1981 Jun 1;195(3):761-4
references.pmid: 7316983
references.citation: Arch Biochem Biophys. 1990 Oct;282(1):183-7
references.pmid: 2171428
references.citation: Biochem Pharmacol. 2007 Jun 1;73(11):1842-51
references.pmid: 17359941
references.citation: Xenobiotica. 1984 Jul;14(7):503-8
references.pmid: 6506762
references.citation: Drug Metab Dispos. 2000 Mar;28(3):360-6
references.pmid: 10681383