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The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s

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The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s. / Potega, Agnieszka; Dabrowska, Emilia; Niemira, Magdalena; Kot-Wasik, Agata; Ronseaux, Sebastien; Henderson, Colin J.; Wolf, C. Roland; Mazerska, Zofia.

In: Drug Metabolism and Disposition, Vol. 39, No. 8, 08.2011, p. 1423-1432.

Research output: Contribution to journalArticle

Harvard

Potega, A, Dabrowska, E, Niemira, M, Kot-Wasik, A, Ronseaux, S, Henderson, CJ, Wolf, CR & Mazerska, Z 2011, 'The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s' Drug Metabolism and Disposition, vol 39, no. 8, pp. 1423-1432., 10.1124/dmd.111.038984

APA

Potega, A., Dabrowska, E., Niemira, M., Kot-Wasik, A., Ronseaux, S., Henderson, C. J., ... Mazerska, Z. (2011). The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s. Drug Metabolism and Disposition, 39(8), 1423-1432. 10.1124/dmd.111.038984

Vancouver

Potega A, Dabrowska E, Niemira M, Kot-Wasik A, Ronseaux S, Henderson CJ et al. The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s. Drug Metabolism and Disposition. 2011 Aug;39(8):1423-1432. Available from: 10.1124/dmd.111.038984

Author

Potega, Agnieszka; Dabrowska, Emilia; Niemira, Magdalena; Kot-Wasik, Agata; Ronseaux, Sebastien; Henderson, Colin J.; Wolf, C. Roland; Mazerska, Zofia / The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s.

In: Drug Metabolism and Disposition, Vol. 39, No. 8, 08.2011, p. 1423-1432.

Research output: Contribution to journalArticle

Bibtex - Download

@article{26cc01647fdb42c980c6baaa4efcb104,
title = "The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s",
keywords = "BIOACTIVATION IN-VITRO, ANTINEOPLASTIC IMIDAZOACRIDINONES, MITOTIC CATASTROPHE, COVALENT BINDING, HUMAN LIVER, INHIBITION, CELLS, DNA, DERIVATIVES, MECHANISM",
author = "Agnieszka Potega and Emilia Dabrowska and Magdalena Niemira and Agata Kot-Wasik and Sebastien Ronseaux and Henderson, {Colin J.} and Wolf, {C. Roland} and Zofia Mazerska",
year = "2011",
doi = "10.1124/dmd.111.038984",
volume = "39",
number = "8",
pages = "1423--1432",
journal = "Drug Metabolism and Disposition",
issn = "0090-9556",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s

A1 - Potega,Agnieszka

A1 - Dabrowska,Emilia

A1 - Niemira,Magdalena

A1 - Kot-Wasik,Agata

A1 - Ronseaux,Sebastien

A1 - Henderson,Colin J.

A1 - Wolf,C. Roland

A1 - Mazerska,Zofia

AU - Potega,Agnieszka

AU - Dabrowska,Emilia

AU - Niemira,Magdalena

AU - Kot-Wasik,Agata

AU - Ronseaux,Sebastien

AU - Henderson,Colin J.

AU - Wolf,C. Roland

AU - Mazerska,Zofia

PY - 2011/8

Y1 - 2011/8

N2 - <p>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.</p>

AB - <p>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.</p>

KW - BIOACTIVATION IN-VITRO

KW - ANTINEOPLASTIC IMIDAZOACRIDINONES

KW - MITOTIC CATASTROPHE

KW - COVALENT BINDING

KW - HUMAN LIVER

KW - INHIBITION

KW - CELLS

KW - DNA

KW - DERIVATIVES

KW - MECHANISM

U2 - 10.1124/dmd.111.038984

DO - 10.1124/dmd.111.038984

M1 - Article

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

SN - 0090-9556

IS - 8

VL - 39

SP - 1423

EP - 1432

ER -

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