Cytosol mediated metabolism of the experimental antitumor agent acridine carboxamide to the 9-acridone derivative.
The acridine antitumor agent N-[2'-(dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601316; acridine carboxamide) is oxidized efficiently in vitro by rat and mouse hepatic cytosolic fractions. Under these conditions the oxidase activity has an apparent Km of 11 microM towards AC. A single product is formed which has been identified as the corresponding 9(10H)-acridone carboxamide by 1H-NMR and mass spectrometry. Inhibition with menadione and amsacrine, but not allopurinol, indicates that this reaction is most likely to be catalysed by aldehyde oxidase (EC 1.2.3.1). Several AC analogues with modifications to the side chain (the N-oxide, N-monomethyl-, and amino-derivatives) are also metabolized to the equivalent acridone product but the 7-hydroxylated and 4-carboxylic acid acridine derivatives are not.
Robertson
I G
IG
Department of Pharmacology and Clinical Pharmacology, University of Auckland School of Medicine, New Zealand.
Palmer
B D
BD
Officer
M
M
Siegers
D J
DJ
Paxton
J W
JW
Shaw
G J
GJ
D000166:Acridines; D000609:Aminoacridines / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000378:metabolism
D000166:Acridines; D000609:Aminoacridines; D000970:Antineoplastic Agents; C071880:9(10H)-acridone carboxamide; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide