title: Flavin monooxygenases, FMO1 and FMO3, not cytochrome P450 isoenzymes, contribute to metabolism of anti-tumour triazoloacridinone, C-1305, in liver microsomes and HepG2 cells.
abstract: 5-Dimethylaminopropylamino-8-hydroxytriazoloacridinone, C-1305, being the close structural analogue of the clinically tested imidazoacridinone anti-tumour agent, C-1311, expressed high activity against experimental tumours and is expected to have more advantageous pharmacological properties than C-1311.        The aim of this study was to elucidate the role of selected liver enzymes in the metabolism of C-1305.        We demonstrated that the studied triazoloacridinone was transformed with rat and human liver microsomes, HepG2 hepatoma cells and with human recombinant flavin-containing monooxygenases FMO1, FMO3 but not with CYPs. Furthermore, this compound was an effective inhibitor of CYP1A2 and CYP3A4. The product of FMO catalysed metabolism was shown to be identical to the main metabolite from liver microsomes and HepG2 cells. It was identified as an N-oxide derivative and, under hypoxia, it underwent retroreduction back to C-1305, what was extremely effective with participation of CYP3A4.        In summary, this work revealed that the involvement of the P450 enzymatic system in microsomal and cellular metabolism of C-1305 was negligible, whereas this agent was an inhibitor of CYP1A2 and CYP3A4. In contrast, FMO1 and FMO3 were crucial for metabolism of C-1305 by liver microsomes and in HepG2 cells, which makes C-1305 an attractive potent anti-tumour agent.
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Gdańsk University of Technology, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Fedejko-Kap
authors.forename: Magdalena
authors.initials: M
authors.lastname: Niemira
authors.forename: Anna
authors.initials: A
authors.lastname: Radominska-Pandya
authors.forename: Zofia
authors.initials: Z
authors.lastname: Mazerska
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000609:Aminoacridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D055162:Biocatalysis / Q000187:drug effects; D001711:Biotransformation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010105:Oxygenases / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D014019:Tissue Donors; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000166:Acridines; D000609:Aminoacridines; D000970:Antineoplastic Agents; C488734:C 1305; D007527:Isoenzymes; D011994:Recombinant Proteins; D014230:Triazoles; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C098965:C 1311