Imidazoacridinone antitumor agent C-1311 as a selective mechanism- based inactivator of human cytochrome P450 1A2 and 3A4 isoenzymes. - Publikacja - MOST Wiedzy

Twoje konto

zaloguj

Wyszukiwarka

Imidazoacridinone antitumor agent C-1311 as a selective mechanism- based inactivator of human cytochrome P450 1A2 and 3A4 isoenzymes.

Abstrakt

5-Diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311), a promising antitumor agent that is also active against autoimmune diseases, was determined to be a selective inhibitor of the cytochrome P450 (CYP) 1A2 and 3A4 isoenzymes. Therefore, C-1311 might modulate the effectiveness of other drugs used in multidrug therapy. The present work aimed to identify the mechanism of the observed C-1311-mediated inactivation of CYP1A2 and CYP3A4. The inactivation experiments were performed in vitro using the human recombinant CYP1A2 and CYP3A4 (Bactosomes). CYP isoenzyme activities were determined using the CYP-specific reactions, 7-ethoxycoumarin O-deethylation (CYP1A2) and testosterone 6β-hydroxylation (CYP3A4). The concentrations of CYP-specific substrates and their metabolites formed by CYP isoenzymes were measured by RP-HPLC with UV-Vis detection. The inhibition of CYPs by C-1311 was time-, concentration- and NADPH-dependent, which suggested a mechanism-based mode of action. Using a 10-fold dilution method and potassium ferricyanide we demonstrated the irreversible nature of the inhibition. In addition, the inhibition was attenuated by the presence of alternate substrates (alternative active site ligands) but not by a nucleophilic trapping agent (glutathione) or a reactive oxygen scavenger (catalase), which further supported a mechanism-based action. Substrate depletion partition ratios of 299 and 985 were calculated for the inactivation of CYP1A2 and CYP3A4, respectively. Our results indicated that C-1311 is a potent mechanism-based inactivator of CYP1A2 and CYP3A4. This finding provided new insights into the mechanism of C-1311 antitumor action, particularly in relation to potential pharmacokinetic drug–drug interactions between C-1311 and/or its derivatives and the substrates of CYP isoforms.

Cytowania

  • 6

    CrossRef

  • 0

    Web of Science

  • 7

    Scopus

Autorzy (3)

Cytuj jako

Pełna treść

pobierz publikację
pobrano 15 razy
Wersja publikacji
Accepted albo Published Version
DOI:
Cyfrowy identyfikator dokumentu elektronicznego (otwiera się w nowej karcie) 10.1016/j.pharep.2016.02.003
Licencja
Creative Commons: CC-BY-NC-ND otwiera się w nowej karcie

Słowa kluczowe

Informacje szczegółowe

Kategoria:
Publikacja w czasopiśmie
Typ:
artykuł w czasopiśmie wyróżnionym w JCR
Opublikowano w:
Pharmacological Reports nr 68, wydanie 4, strony 663 - 670,
ISSN: 1734-1140
Język:
angielski
Rok wydania:
2016
Opis bibliograficzny:
Potęga A., Fedejko-Kap, B., Mazerska Z.: Imidazoacridinone antitumor agent C-1311 as a selective mechanism- based inactivator of human cytochrome P450 1A2 and 3A4 isoenzymes.// Pharmacological Reports. -Vol. 68, iss. 4 (2016), s.663-670
DOI:
Cyfrowy identyfikator dokumentu elektronicznego (otwiera się w nowej karcie) 10.1016/j.pharep.2016.02.003
Weryfikacja:
Politechnika Gdańska

wyświetlono 116 razy

Publikacje, które mogą cię zainteresować

Mechanism-based inactivation of human cytochrome P450 1A2 and 3A4 isoenzymes by antitumor triazoloacridinone C-1305.

2016

Drug-drug interaction potential of antitumor acridine agent C-1748: The substrate of UDP-glucuronosyltransferases 2B7, 2B17 and the inhibitor of 1A9 and 2B7

2018

Metabolic Profiles of New Unsymmetrical Bisacridine Antitumor Agents in Electrochemical and Enzymatic Noncellular Systems and in Tumor Cells

2021

Modulation of UDP-glucuronidation by acridinone antitumor agents C-1305 and C-1311 in HepG2 and HT29 cell lines, despite slight impact in noncellular systems.

2018
Meta Tagi