title: The imidazoacridinone antitumor drug, C-1311, is metabolized by flavin monooxygenases but not by cytochrome P450s.
abstract: 5-Diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) is an antitumor agent that is also active against autoimmune diseases. The intention of the present studies was to elucidate the role of selected liver enzymes in metabolism of C-1311 and the less active 8-methyl derivative, 5-diethylaminoethylamino-8-methoxyimidazoacridinone (C-1330). Compounds were incubated with rat liver microsomal fraction, with a set of 16 human liver protein samples, and with human recombinant isoenzymes of cytochrome P450, flavin monooxygenases (FMO), and UDP-glucuronosyltransferase (UGT). Our results showed that C-1311 and C-1330 were metabolized with human liver microsomal enzymes but not with any tested human recombinant cytochromes P450 (P450s). Two of these, CYP1A2 and CYP3A4, were inhibited by both compounds. In addition, results of C-1311 elimination from hepatic reductase-null mice, in which liver NADPH-P450 oxidoreductase has been deleted indicated that liver P450s were slightly engaged in drug transformation. In contrast, both compounds were good substrates for human recombinant FMO1 and FMO3 but not for FMO5. The product of FMO metabolism, P(FMO), which is identified as an N-oxide derivative, was identical to P3(R) of liver microsomes. P3(R) was observed even in the presence of the P450 inhibitor, 1-aminobenzotriazole, and it disappeared after heating. Therefore, FMO enzymes could be responsible for microsomal metabolism to P3(R) = P(FMO). Glucuronidation on the 8-hydroxyl group of C-1311 was observed with liver microsomes supported by UDP-glucuronic acid and with recombinant UGT1A1, but it was not the case with UGT2B7. Summing up, we showed that, whereas liver P450 isoenzymes were involved in the metabolism of C-1311 to a limited extent, FMO plays a significant role in the microsomal transformations of this compound, which is also a specific substrate of UGT1A1.
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdańsk University of Technology, Gdansk, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Potega
authors.forename: Emilia
authors.initials: E
authors.lastname: Dabrowska
authors.forename: Magdalena
authors.initials: M
authors.lastname: Niemira
authors.forename: Agata
authors.initials: A
authors.lastname: Kot-Wasik
authors.forename: Sebastien
authors.initials: S
authors.lastname: Ronseaux
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Henderson
authors.forename: C Roland
authors.initials: CR
authors.lastname: Wolf
authors.forename: Zofia
authors.initials: Z
authors.lastname: Mazerska
mesh_terms: D000609:Aminoacridines / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D007527:Isoenzymes; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D013379:Substrate Specificity
chemical_list: D000609:Aminoacridines; D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C098965:C 1311