Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

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

11/01/1985

Pubmed ID

4062959

DOI

10.1016/0006-2952(85)90433-2

Scopus ID

2-s2.0-0022380022 (requires institutional sign-in at Scopus site)   14 Citations

Abstract

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 B

Author

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
Biotransformation
DNA
Imides
In Vitro Techniques
Isoquinolines
Male
Microsomes, Liver
Naphthalimides
Oxygen Consumption
Rats
Rats, Inbred Strains