THE HYDROLYSIS PRODUCT OF ICRF-187 PROMOTES IRON-CATALYZED HYDROXYL RADICAL PRODUCTION VIA THE FENTON REACTION

Citation
C. Thomas et al., THE HYDROLYSIS PRODUCT OF ICRF-187 PROMOTES IRON-CATALYZED HYDROXYL RADICAL PRODUCTION VIA THE FENTON REACTION, Biochemical pharmacology, 45(10), 1993, pp. 1967-1972
Citations number
35
Categorie Soggetti
Pharmacology & Pharmacy",Biology
Journal title
ISSN journal
00062952
Volume
45
Issue
10
Year of publication
1993
Pages
1967 - 1972
Database
ISI
SICI code
0006-2952(1993)45:10<1967:THPOIP>2.0.ZU;2-C
Abstract
d-1,2-Bis(3,5-dioxopiperazine-1-yl)propane (ICR.F-187) (ADR-529) is a drug that ameliorates the cardiotoxicity of Adriamycin(R). The drug en ters cells where hydrolysis leads to its diacid diamide product, midom ethyl-N,N'-dicarboxymethyl-1,2-diaminopropane (ICRF-198) (ADR-925), wh ich is structurally similar to ethylenediaminetetraacetic acid (EDTA). The protective mechanism of ICRF-187 is unknown, but a plausible expl anation is that ICRF-198 chelates iron intracellularly to prevent iron -dependent free radical reactions such as hydroxyl radical (.OH) produ ction. We have compared Fe(ICRF-198) with Fe(EDTA) in its ability to p romote .OH formation in several Fenton reaction systems. The Fenton re action was studied with H2O2 and Fe2+ chelates or catalytic amounts of the iron chelates in the presence of Adriamycin radicals, paraquat ra dicals, superoxide anion radicals (O2-), and ascorbate as reducing spe cies. .OH was detected with deoxyribose and dimethyl sulfoxide. The tw o methods gave comparable results. Fe(ICRF-198) was 80-100% as effecti ve as Fe(EDTA) at promoting .OH production in the presence of the orga nic radicals and ascorbate, 30-70% in the presence of O2-, and 150% wi th non-cycling Fe2+. Fe(EDTA) is a more efficient catalyst of .OH prod uction than physiological chelates such as ADP, ATP and citrate. There fore, by comparing previous work which examined physiological chelates and Fe(EDTA) with the present work, Fe(ICRF-198) appears to be a bett er .OH catalyst than the physiological chelates. These results suggest that ICRF-198 generated in vivo from ICRF-187 would not protect again st intracellular .OH production. They also imply that .OH production m ay not be as important in Adriamycin cardiotoxicity as other radical r eactions, such as lipid peroxidation and thiol oxidation, that are inh ibited by ICRF-198.