title: Mechanism-based inactivation of human cytochrome P450 1A2 and 3A4 isoenzymes by anti-tumor triazoloacridinone C-1305.
abstract: 1. 5-Dimethylaminopropylamino-8-hydroxytriazoloacridinone, C-1305, is a promising anti-tumor therapeutic agent with high activity against several experimental tumors. 2. It was determined to be a potent and selective inhibitor of liver microsomal and human recombinant cytochrome P450 (CYP) 1A2 and 3A4 isoenzymes. Therefore, C-1305 might modulate the effectiveness of other drugs used in multidrug therapy. 3. The objective of this study was to investigate the mechanism of the observed C-1305-mediated inactivation of CYP1A2 and CYP3A4. 4. Our findings indicated that C-1305 produced a time- and concentration-dependent decrease in 7-ethoxycoumarin O-deethylation (CYP1A2, KI= 10.8 ± 2.14 μM) and testosterone 6β-hydroxylation (CYP3A4, KI= 9.1 ± 2.82 μM). The inactivation required the presence of NADPH, was unaffected by a nucleophilic trapping agent (glutathione) and a reactive oxygen species scavenger (catalase), attenuated by a CYP-specific substrate (7-ethoxycoumarin or testosterone), and was not reversed by potassium ferricyanide. The estimated partition ratios of 1086 and 197 were calculated for the inactivation of CYP1A2 and CYP3A4, respectively. 5. In conclusion, C-1305 inhibited human recombinant CYP1A2 and CYP3A4 isoenzymes by mechanism-based inactivation. The obtained knowledge about specific interactions between C-1305 and/or its metabolites, and CYP isoforms would be useful for predicting the possible drug-drug interactions in potent multidrug therapy.
authors.affiliation: a Department of Pharmaceutical Technology and Biochemistry , Chemical Faculty, Gdańsk University of Technology , Gdańsk , Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Potęga
authors.affiliation: a Department of Pharmaceutical Technology and Biochemistry , Chemical Faculty, Gdańsk University of Technology , Gdańsk , Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Fedejko-Kap
authors.affiliation: a Department of Pharmaceutical Technology and Biochemistry , Chemical Faculty, Gdańsk University of Technology , Gdańsk , Poland.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Mazerska
mesh_terms: D000166:Acridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; C488734:C 1305; D065607:Cytochrome P-450 Enzyme Inhibitors; D014230:Triazoles; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A
keywords: Anti-tumor agent; C-1305; bioactivation; drug–drug interactions; human CYP isoenzymes; mechanism-based inactivation