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

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

Abstract

5-Dimethylaminopropylamino-8-hydroxytriazoloacridinone, C-1305, is a promising antitumor therapeutic agent with high activity against several experimental tumors. 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. The objective of this study was to investigate the mechanism of the observed C-1305- mediated inactivation of CYP1A2 and CYP3A4. Our findings indicated that C-1305 produced a time- and concentration-dependent decrease in 7-ethoxycoumarin O-deethylation (CYP1A2, KI = 10.8 ± 2.14 mM) and testosterone 6bhydroxylation (CYP3A4, KI = 9.1 ± 2.82 mM). 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. 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.

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DOI:
Digital Object Identifier (open in new tab) 10.3109/00498254.2016.1147623
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Category:
Articles
Type:
artykuł w czasopiśmie wyróżnionym w JCR
Published in:
XENOBIOTICA no. 46, pages 1056 - 1065,
ISSN: 0049-8254
Language:
English
Publication year:
2016
Bibliographic description:
Potęga A., Fedejko-Kap, B., Mazerska Z.: Mechanism-based inactivation of human cytochrome P450 1A2 and 3A4 isoenzymes by antitumor triazoloacridinone C-1305.// XENOBIOTICA. -Vol. 46, nr. 12 (2016), s.1056-1065
DOI:
Digital Object Identifier (open in new tab) 10.3109/00498254.2016.1147623
Verified by:
Gdańsk University of Technology

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