Inhibition by SKF-525A of the aldehyde oxidase-mediated metabolism of the experimental antitumour agent acridine carboxamide.
Oxidation of the experimental anti-tumour agent N-[(2'-dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601316; acridine carboxamide) to the 9(10H)acridone, followed by ring hydroxylation and glucuronidation, appears to be the main pathway of detoxication of AC in the rat and mouse. The acridone formation has been further characterized in vitro using an enzyme-enriched fraction where activity per milligram protein is increased approximately 10-fold compared with the cytosolic fraction. Inhibition by amsacrine [4'-(9-acridinylamino)methanesulphon-m-anisidide; NSC 249992] and menadione (50% inhibition at 6.4 and 1.8 microM, respectively) but not allopurinol (to 30 microM) indicates that the activity is due to aldehyde oxidase, without the involvement of xanthine oxidase. Interestingly, acridone formation in both the cytosolic and enzyme-enriched fractions is highly sensitive to the classical cytochrome P450 inhibitor SKF-525A [proadifen hydrochloride; 2'-(diethylamino)ethyl 2,2-diphenylpentenoate] (50% inhibition at 9.2 and 1.9 microM, respectively). Further analysis indicates mixed non-competitive type inhibition by SKF-525A (K(is), 0.3 microM; K(ii), 4.9 microM). Little or no inhibition was seen with cimetidine, metyrapone or methimazole. No NADPH-dependent acridone formation was observed with the microsomal fraction. These data indicate that acridone formation previously observed in isolated rat hepatocytes and in vivo is most likely due to aldehyde oxidase rather than cytochrome P450.
Department of Pharmacology and Clinical Pharmacology, University of Auckland School of Medicine, New Zealand.
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Bland
D000166:Acridines / Q000378:metabolism; D054831:Acridones; D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000609:Aminoacridines / Q000378:metabolism*; D000677:Amsacrine / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D002927:Cimetidine / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D008713:Methimazole / Q000378:metabolism; D008797:Metyrapone / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology; D009243:NAD / Q000378:metabolism; D011335:Proadifen / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000166:Acridines; D054831:Acridones; D000609:Aminoacridines; D000970:Antineoplastic Agents; D000677:Amsacrine; D009243:NAD; D008713:Methimazole; C041300:acridone; D002927:Cimetidine; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide; D011335:Proadifen; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase; D008797:Metyrapone