A variety of physiological and pathophysiological processes as well as the metabolism of a number of drugs proceed through complex oxidative mechanisms in which transient, highly reactive intermediates such as superoxide anion, hydroxyl radical and singlet molecular oxygen play a major role. The ability to develop novel therapeutic approaches to modify these medically important processes requires a detailed knowledge of the identity of the intermediates involved, their concentrations and how these concentrations vary with experimental conditions. Of the intermediates most commonly postulated to be important, information about singlet molecular oxygen is particularly deficient. Instrumentation developed in this laboratory (using the characteristic infrared emission band of singlet oxygen at 1268 nm) provides a means to detect singlet oxygen in complex biological systems for the first time (J Biol Chem 258:5991-5993, 1983). Studies of singlet oxygen production by a number of anti- neoplastic drugs and related compounds will becarried out. Compounds to be studied include bleomycin, doxorubicin, daunorubicin, carminic acid, mithramycin, chromomycin A3, olivomycin, mitomycin C, VP-16 streptonigrin, procarbazine, paraquat, cis-platinum and gossypol. Preliminary studies in this laboratory have demonstrated signlet oxygen production by the bleomycin-ferric-ion-13- hydroperoxylinoleic acid system. Singlet oxygen production in this system will be correlated with the quantity and type of DNA degradation in model systems and with the ability to cause destructive lipid peroxidation in red blood cell ghosts. The mechanism of singlet oxygen in liver microsomes supplemented with 13-hydro-peroxylinoleic acid will be determined. Studies with purified cytochrome P-450 will also be done. Measurements of singlet oxygen production by prostaglandin synthestase will be made. prior studies have shown that lipoxygenases produce singlet oxygen. A search for singlet oxygen emission in the asbestos-fiber- catalyzed decomposition of hydrogen peroxide will be made.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM032974-06
Application #
3282248
Study Section
Biophysics and Biophysical Chemistry A Study Section (BBCA)
Project Start
1983-12-01
Project End
1990-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Edward Hines Jr VA Hospital
Department
Type
DUNS #
City
Hines
State
IL
Country
United States
Zip Code
60141
Kanofsky, J R; Sima, P (1991) Singlet oxygen production from the reactions of ozone with biological molecules. J Biol Chem 266:9039-42
Kanofsky, J R (1991) Singlet oxygen production from the reactions of superoxide ion in aprotic solvents: implications for hydrophobic biochemistry. Free Radic Res Commun 12-13 Pt 1:87-92
Baker, A; Kanofsky, J R (1991) Direct observation of singlet oxygen phosphorescence at 1270 nm from L1210 leukemia cells exposed to polyporphyrin and light. Arch Biochem Biophys 286:70-5
Kanofsky, J R (1991) Quenching of singlet oxygen by human red cell ghosts. Photochem Photobiol 53:93-9
Everett, R R; Kanofsky, J R; Butler, A (1990) Mechanistic investigations of the novel non-heme vanadium bromoperoxidases. Evidence for singlet oxygen production. J Biol Chem 265:4908-14
Kanofsky, J R (1990) Quenching of singlet oxygen by human plasma. Photochem Photobiol 51:299-303
Kanofsky, J R (1989) Bromine derivatives of amino acids as intermediates in the peroxidase-catalyzed formation of singlet oxygen. Arch Biochem Biophys 274:229-34
Kanofsky, J R (1989) Singlet oxygen production by biological systems. Chem Biol Interact 70:1-28
Kanofsky, J R (1989) Singlet oxygen production from the peroxidase catalyzed formation of styrene glutathione adducts. Biochem Biophys Res Commun 159:1051-4
Kanofsky, J R; Hoogland, H; Wever, R et al. (1988) Singlet oxygen production by human eosinophils. J Biol Chem 263:9692-6

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