Mechanism of DNA strand breaks by mitonafide, an imide derivative of 3-nitro-1,8-naphthalic acid. Biochem Pharmacol 1985 Nov 01;34(21):3845-52
Date
11/01/1985Pubmed ID
4062959DOI
10.1016/0006-2952(85)90433-2Scopus ID
2-s2.0-0022380022 (requires institutional sign-in at Scopus site) 14 CitationsAbstract
The metabolism and the mechanism of action of 5-nitro-2-(2-dimethylaminoethyl)-benzo(de) isoquinoline-1,3-dione (mitonafide), a nitro-containing antitumor drug, have been studied. Incubation of mitonafide under anaerobic conditions with rat liver microsomes and NADPH formed the fully reduced amine metabolite, 5-aminomitonafide. The formation of the amine metabolite was not inhibited by SKF-525A, metyrapone or piperonyl butoxide, indicating that the cytochrome P-450 was not involved in this reduction. Incubation of mitonafide with rat liver microsomes and NADPH under aerobic conditions stimulated oxygen consumption; piperonyl butoxide, SKF-525A, superoxide dismutase and catalase had no effect on this stimulation. Both mitonafide and 5-aminomitonafide were found to bind to DNA in a similar manner. However, in inducing single-stand breaks in the DNA of L1210 cells mitonafide was 10-fold more potent than 5-aminomitonafide. These results suggest that metabolic activation of mitonafide to species other than that of the amine metabolite may play a significant role in the induction of DNA damage and the biological activity of the drug.
Author List
Sinha BK, Strong J, Gibson NW, Kalyanaraman BAuthor
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents
Biotransformation
DNA
Imides
In Vitro Techniques
Isoquinolines
Male
Microsomes, Liver
Naphthalimides
Oxygen Consumption
Rats
Rats, Inbred Strains