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Generation of free radicals from neocarzinostatin mediated by NADPH/cytochrome P-450 reductase via activation of enediyne chromophore. 1994

K Sato, and T Akaike, and M Suga, and M Ando, and H Maeda
Department of Microbiology, Kumamoto University School of Medicine, Japan.

Neocarzinostatin (NCS) is one of the most potent antitumor agents. It contains a chromophore of a unique enediyne structure as its prosthetic group. Here, we report the generation of free radicals from NCS by the NADPH/cytochrome (cyt) P-450 reductase system. Free radical species, which were generated in the reaction mixture of NCS/NADPH/cyt P-450 reductase, were identified by using electron spin resonance spin trapping with 5,5-dimethyl-1-pyrroline N-oxide (DMPO). The spin adducts of superoxide and hydroxyl radical (DMPO-OOH and DMPO-OH, respectively) were generated in the reaction of NCS with the NADPH/cyt P-450 reductase system. From kinetic analyses of DMPO-OOH generation as a function of the concentration of NCS, the Vmax/Km value of the reaction was 0.4 x 10(6) M-1min-1. In addition, we identified thiyl radical generation in this system in the presence of glutathione. These results indicate that NCS is a potent generator of free radicals in cells where cyt P-450 reductase is available. Moreover, it seems that free radicals, generated by enzymatic activation of NCS, are involved in cytotoxicity of NCS as well as in DNA damage.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D009251 NADPH-Ferrihemoprotein Reductase A flavoprotein that catalyzes the reduction of heme-thiolate-dependent monooxygenases and is part of the microsomal hydroxylating system. EC 1.6.2.4. Cytochrome P-450 Reductase,Ferrihemoprotein P-450 Reductase,NADPH Cytochrome P-450 Oxidoreductase,NADPH Cytochrome P-450 Reductase,NADPH Cytochrome c Reductase,Cytochrome P-450 Oxidase,Cytochrome P450 Reductase,Ferrihemoprotein P450 Reductase,NADPH Cytochrome P450 Oxidoreductase,NADPH Cytochrome P450 Reductase,NADPH-Cytochrome P450 Reductase,NADPH-P450 Reductase,Cytochrome P 450 Oxidase,Cytochrome P 450 Reductase,Ferrihemoprotein P 450 Reductase,NADPH Cytochrome P 450 Oxidoreductase,NADPH Cytochrome P 450 Reductase,NADPH Ferrihemoprotein Reductase,NADPH P450 Reductase,Oxidase, Cytochrome P-450,P-450 Oxidase, Cytochrome,P450 Reductase, Cytochrome,P450 Reductase, NADPH-Cytochrome,Reductase, Cytochrome P-450,Reductase, Cytochrome P450,Reductase, Ferrihemoprotein P-450,Reductase, Ferrihemoprotein P450,Reductase, NADPH-Cytochrome P450,Reductase, NADPH-Ferrihemoprotein,Reductase, NADPH-P450
D009353 Zinostatin An enediyne that alkylates DNA and RNA like MITOMYCIN does, so it is cytotoxic. Neocarzinostatin
D003497 Cyclic N-Oxides Heterocyclic compounds in which an oxygen is attached to a cyclic nitrogen. Heterocyclic N-Oxides,Cyclic N Oxides,Heterocyclic N Oxides,N Oxides, Cyclic,N-Oxides, Cyclic,N-Oxides, Heterocyclic,Oxides, Cyclic N
D004578 Electron Spin Resonance Spectroscopy A technique applicable to the wide variety of substances which exhibit paramagnetism because of the magnetic moments of unpaired electrons. The spectra are useful for detection and identification, for determination of electron structure, for study of interactions between molecules, and for measurement of nuclear spins and moments. (From McGraw-Hill Encyclopedia of Science and Technology, 7th edition) Electron nuclear double resonance (ENDOR) spectroscopy is a variant of the technique which can give enhanced resolution. Electron spin resonance analysis can now be used in vivo, including imaging applications such as MAGNETIC RESONANCE IMAGING. ENDOR,Electron Nuclear Double Resonance,Electron Paramagnetic Resonance,Paramagnetic Resonance,Electron Spin Resonance,Paramagnetic Resonance, Electron,Resonance, Electron Paramagnetic,Resonance, Electron Spin,Resonance, Paramagnetic
D005609 Free Radicals Highly reactive molecules with an unsatisfied electron valence pair. Free radicals are produced in both normal and pathological processes. Free radicals include reactive oxygen and nitrogen species (RONS). They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation, damage from environment chemicals, and aging. Natural and pharmacological prevention of free radical damage is being actively investigated. Free Radical
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013113 Spin Labels Molecules which contain an atom or a group of atoms exhibiting an unpaired electron spin that can be detected by electron spin resonance spectroscopy and can be bonded to another molecule. (McGraw-Hill Dictionary of Chemical and Technical Terms, 4th ed) Spin Label,Label, Spin,Labels, Spin
D016923 Cell Death The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. Death, Cell

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