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Diminished toxicity of C-1748, 4-methyl-9-hydroxyethylamino-1-nitroacridine, compared with its demethyl analog, C-857, corresponds to its resistance to metabolism in HepG2 cells

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Diminished toxicity of C-1748, 4-methyl-9-hydroxyethylamino-1-nitroacridine, compared with its demethyl analog, C-857, corresponds to its resistance to metabolism in HepG2 cells. / Wisniewska, Anita; Niemira, Magdalena; Jagiello, Karolina; Potega, Agnieszka; Swist, Malgorzata; Henderson, Colin; Skwarska, Anna; Augustin, Ewa; Konopa, Jerzy; Mazerska, Zofia.

In: Biochemical Pharmacology, Vol. 84, No. 1, 01.07.2012, p. 30-42.

Research output: Contribution to journalArticle

Harvard

Wisniewska, A, Niemira, M, Jagiello, K, Potega, A, Swist, M, Henderson, C, Skwarska, A, Augustin, E, Konopa, J & Mazerska, Z 2012, 'Diminished toxicity of C-1748, 4-methyl-9-hydroxyethylamino-1-nitroacridine, compared with its demethyl analog, C-857, corresponds to its resistance to metabolism in HepG2 cells' Biochemical Pharmacology, vol 84, no. 1, pp. 30-42., 10.1016/j.bcp.2012.03.013

APA

Wisniewska, A., Niemira, M., Jagiello, K., Potega, A., Swist, M., Henderson, C., ... Mazerska, Z. (2012). Diminished toxicity of C-1748, 4-methyl-9-hydroxyethylamino-1-nitroacridine, compared with its demethyl analog, C-857, corresponds to its resistance to metabolism in HepG2 cells. Biochemical Pharmacology, 84(1), 30-42. 10.1016/j.bcp.2012.03.013

Vancouver

Wisniewska A, Niemira M, Jagiello K, Potega A, Swist M, Henderson C et al. Diminished toxicity of C-1748, 4-methyl-9-hydroxyethylamino-1-nitroacridine, compared with its demethyl analog, C-857, corresponds to its resistance to metabolism in HepG2 cells. Biochemical Pharmacology. 2012 Jul 1;84(1):30-42. Available from: 10.1016/j.bcp.2012.03.013

Author

Wisniewska, Anita; Niemira, Magdalena; Jagiello, Karolina; Potega, Agnieszka; Swist, Malgorzata; Henderson, Colin; Skwarska, Anna; Augustin, Ewa; Konopa, Jerzy; Mazerska, Zofia / Diminished toxicity of C-1748, 4-methyl-9-hydroxyethylamino-1-nitroacridine, compared with its demethyl analog, C-857, corresponds to its resistance to metabolism in HepG2 cells.

In: Biochemical Pharmacology, Vol. 84, No. 1, 01.07.2012, p. 30-42.

Research output: Contribution to journalArticle

Bibtex - Download

@article{c395c051ddfc4b51b0b47699ae722edf,
title = "Diminished toxicity of C-1748, 4-methyl-9-hydroxyethylamino-1-nitroacridine, compared with its demethyl analog, C-857, corresponds to its resistance to metabolism in HepG2 cells",
author = "Anita Wisniewska and Magdalena Niemira and Karolina Jagiello and Agnieszka Potega and Malgorzata Swist and Colin Henderson and Anna Skwarska and Ewa Augustin and Jerzy Konopa and Zofia Mazerska",
year = "2012",
doi = "10.1016/j.bcp.2012.03.013",
volume = "84",
number = "1",
pages = "30--42",
journal = "Biochemical Pharmacology",
issn = "0006-2952",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Diminished toxicity of C-1748, 4-methyl-9-hydroxyethylamino-1-nitroacridine, compared with its demethyl analog, C-857, corresponds to its resistance to metabolism in HepG2 cells

A1 - Wisniewska,Anita

A1 - Niemira,Magdalena

A1 - Jagiello,Karolina

A1 - Potega,Agnieszka

A1 - Swist,Malgorzata

A1 - Henderson,Colin

A1 - Skwarska,Anna

A1 - Augustin,Ewa

A1 - Konopa,Jerzy

A1 - Mazerska,Zofia

AU - Wisniewska,Anita

AU - Niemira,Magdalena

AU - Jagiello,Karolina

AU - Potega,Agnieszka

AU - Swist,Malgorzata

AU - Henderson,Colin

AU - Skwarska,Anna

AU - Augustin,Ewa

AU - Konopa,Jerzy

AU - Mazerska,Zofia

PY - 2012/7/1

Y1 - 2012/7/1

N2 - The narrow "therapeutic window" of anti-tumour therapy may be the result of drug metabolism leading to the activation or detoxification of antitumour agents. The aim of this work is to examine (i) whether the diminished toxicity of a potent antitumour drug, C-1748, 9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine, compared with its 4-demethyl analogue, C-857, results from the differences between the metabolic pathways for the two compounds and (ii) the impact of reducing and/or hypoxic conditions on studied metabolism. We investigated the metabolites of C-1748 and C-857 formed in rat and human liver microsomes, with human P450 reductase (POR) and in HepG2 cells under normoxia and hypoxia. The elimination rate of C-1748 from POR knockout mice (HRN) was also evaluated. Three products, 1-amino-9-hydroxyethylaminoacridine, 1-aminoacridinone and a compound with an additional 6-membered ring, were identified for C-1748 and C-857 in all studied metabolic systems. The new metabolite was found in HepG2 cells. We showed that metabolic rate and the reactivity of metabolites of C-1748 were considerably lower than those of C-857, in all investigated metabolic models. Compared with metabolism under normoxia, cellular metabolism under hypoxia led to higher levels of 1-aminoacridine and aza-acridine derivatives of both compounds and of the 6-membered ring metabolite of C-1748. In conclusion, the crucial role of hypoxic conditions and the direct involvement of POR in the metabolism of both compounds were demonstrated. Compared with C-857, the low reactivity of C-1748 and the stability of its metabolites are postulated to contribute significantly to the diminished toxicity of this compound observed in animals. (c) 2012 Elsevier Inc. All rights reserved.</p>

AB - The narrow "therapeutic window" of anti-tumour therapy may be the result of drug metabolism leading to the activation or detoxification of antitumour agents. The aim of this work is to examine (i) whether the diminished toxicity of a potent antitumour drug, C-1748, 9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine, compared with its 4-demethyl analogue, C-857, results from the differences between the metabolic pathways for the two compounds and (ii) the impact of reducing and/or hypoxic conditions on studied metabolism. We investigated the metabolites of C-1748 and C-857 formed in rat and human liver microsomes, with human P450 reductase (POR) and in HepG2 cells under normoxia and hypoxia. The elimination rate of C-1748 from POR knockout mice (HRN) was also evaluated. Three products, 1-amino-9-hydroxyethylaminoacridine, 1-aminoacridinone and a compound with an additional 6-membered ring, were identified for C-1748 and C-857 in all studied metabolic systems. The new metabolite was found in HepG2 cells. We showed that metabolic rate and the reactivity of metabolites of C-1748 were considerably lower than those of C-857, in all investigated metabolic models. Compared with metabolism under normoxia, cellular metabolism under hypoxia led to higher levels of 1-aminoacridine and aza-acridine derivatives of both compounds and of the 6-membered ring metabolite of C-1748. In conclusion, the crucial role of hypoxic conditions and the direct involvement of POR in the metabolism of both compounds were demonstrated. Compared with C-857, the low reactivity of C-1748 and the stability of its metabolites are postulated to contribute significantly to the diminished toxicity of this compound observed in animals. (c) 2012 Elsevier Inc. All rights reserved.</p>

U2 - 10.1016/j.bcp.2012.03.013

DO - 10.1016/j.bcp.2012.03.013

M1 - Article

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 1

VL - 84

SP - 30

EP - 42

ER -

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