Antitumor imidazoacridinone derivative developed in our group, compound C‑1311 (Symadex^R), is currently under Phase II clinical trials. Multiple studies have shown that metabolic activation is necessary for the following interactions of this agent with proteins and/or DNA in tumor cells. The pathway of C-1311 metabolism in vitro with rat and human liver microsomes was reported previously. However, the incubation of the studied compound with human E. coli recombinant cytochrome P450 isoenzymes (CYPs): 1A2, 2C9, 2C19, 2D6 and 3A4 did not result in any metabolic product. Furthemore, C-1311 turned out to be the inhibitor of the selected CYPs. Hence, the aim of the presented work is to elucidate the mechanism of inhibition induced by C-1311 towards CYP1A2.

Standard CYP1A2 substrate, imipramine, was incubated with human E. coli recombinant CYP1A2 with or without earlier incubation with C‑1311. CYP1A2 was coexpressed with both low and high level of NADPH-cytochrome P450 reductase (CPR). Preincubations with C-1311 were carried out in the presence or in the absence of NADPH and with or without of ten-fold dilution of the reaction mixtures. The rates of substrate metabolism were calculated on the basis of the surface area of the substrate and the main metabolite HPLC peaks. We found that C-1311 significantly inhibited CYP1A2 activity. The loss of the catalytic activity of the above-mentioned enzyme was shown to be time- and concentration dependent as well as needed previous metabolic activation of C-1311. What is more, it could not be restored after dilution.

In conclusion, C-1311 has been shown to be an irreversible and mechanism-based (suicide) inactivator of human CYP1A2. Suicide inhibition of this enzyme by C-1311 may explain the observed earlier resistance of this compound to catalytic action of CYP1A2. The obtained results contribute to better prediction of C-1311-other drug interactions for the design of directed individual therapy in clinical trials.

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/10942 must be provided.

1. Glucuronidation of antitumor agents - detoxification, mechanism of drug resistance or the prodrug design? Studies on acridine antitumor agents in the light of clinical therapeutics
2. Antitumor triazoloacridinone C-1305 as a potent FLT3 tyrosine kinase inhibitor in human leukemia MV4;11 cells.
3. Polymorphism and the level of P450 gene expression in drug metabolism
4. Metabolism of antitumor 9-amino-1-nitroacridine derivative C-1748 (Capridine-beta) in human hepatoma HepG2 cells
5. Specific metabolism of antitumor agents with cytochrome P-450 isoenzymes
6. The role of hepatic cytochrome P-450 enzymes in metabolism of imidazoacridinone antitumor agent, C1311 (Symadex^R): studies with the hepatic NADPH:cytochrome P450 reductase null mice
7. Metabolic transformations of antitumor agents with cytochrome P-450 isoenzymes
8. Effects on cell cycle distribution and induction of apoptosis of human breast carcinoma MCF7 cells by imidazoacridinone C-1311
9. The cellular response of human hepatoma cells with different expression of cytochrome P450 isoenzymes to treatment with acridine derivatives
10. The role of Cytochrome P450 Reductase in metabolism of potent nitroacridine antitumor agent, C‑1748.
11. The cellular response of human colon carcinoma HCT116 cells to 4-methyl-1-nitroacridine derivative C-1748 treatment depending on p53 status.
12. METABOLIC TRANSFORMATIONS OF ANTITUMOR AGENTS WITH CYTOCHROME P-450 ISOENZYMES.