title: CYP1A2-mediated biotransformation of cardioactive 2-thienylidene-3,4-methylenedioxybenzoylhydrazine (LASSBio-294) by rat liver microsomes and human recombinant CYP enzymes.
abstract: We describe herein the metabolic fate of cardioactive 1,3-benzodioxolyl N-acylhydrazone prototype LASSBio-294 (4) and the structural identification of its major phase I metabolite from rat liver microsomal assays. Our results confirmed the hard-metabolic character of N-acylhydrazone (NAH) framework of LASSBio-294 (4). The development of a reproducible analytical methodology for the major metabolite by using HPLC-MS and the comparison with an authentic synthetic sample, allowed us to identify 2-thienylidene 3,4-dihydroxybenzoylhydrazine derivative (7), formed by oxidative scission of methylenedioxy bridge of LASSBio-294, as the main metabolite formed by action of CYP1A2 isoform. The identification of this isoform in the LASSBio-294 in the clearance of LASSBio-294 (4) oxidation was performed by the use of selective CYP inhibitors or human recombinant CYP enzymes.
authors.affiliation: Laboratório de Avaliação e Síntese de Substâncias Bioativas(1), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, RJ 21941-902, PO Box 68006, Brazil.
authors.forename: Aline Guerra M
authors.initials: AG
authors.lastname: Fraga
authors.forename: Leandro Louback
authors.initials: LL
authors.lastname: da Silva
authors.forename: Carlos Alberto Manssour
authors.initials: CA
authors.lastname: Fraga
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
mesh_terms: D000818:Animals; D001711:Biotransformation; D020134:Catalytic Domain; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D008958:Models, Molecular; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism*; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D006835:Hydrazones; C439284:LASSBio 294; D011994:Recombinant Proteins; D013876:Thiophenes; D019388:Cytochrome P-450 CYP1A2