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.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Chemical Faculty, Gdańsk University of Technology, Narutowicza Street 11/12, 80-233 Gdańsk, Poland. awisniewska2@gmail.com.pl
authors.forename: Anita
authors.initials: A
authors.lastname: Wiśniewska
authors.forename: Magdalena
authors.initials: M
authors.lastname: Niemira
authors.forename: Karolina
authors.initials: K
authors.lastname: Jagiełło
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Potęga
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Swist
authors.forename: Colin
authors.initials: C
authors.lastname: Henderson
authors.forename: Anna
authors.initials: A
authors.lastname: Skwarska
authors.forename: Ewa
authors.initials: E
authors.lastname: Augustin
authors.forename: Jerzy
authors.initials: J
authors.lastname: Konopa
authors.forename: Zofia
authors.initials: Z
authors.lastname: Mazerska
mesh_terms: D000609:Aminoacridines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001711:Biotransformation; D018929:Cell Culture Techniques; D015687:Cell Hypoxia / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics / Q000502:physiology; D009564:Nitracrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: C104852:1-nitro-9-(2'-hydroxyethylamino)acridine hydrochloride; C513812:9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine; D000609:Aminoacridines; D000970:Antineoplastic Agents; D009564:Nitracrine; D009251:NADPH-Ferrihemoprotein Reductase