Catechol (estrogen)s and quinones are (co)carcinogens and promoters of carcinogenesis. They are present in tobacco smoke and in animal feeds. Diethylstilbestrol is the most widely used estrogen. In utero exposure to synthetic estrogens causes teratogenic effects. Catechol(amine)s find use in medicine in the treatment of Parkinsonism, hypertension, and cancer. Their side effects include hepatic injury, cardiotoxicity, and photosensitivity. VP-16, a phenolic derivative of podophyllotoxin, is an effective anti-neoplastic agent against small cell carcinoma of the lung. VP-16 is cytotoxic and also causes DNA damage. Production of free radical(s) and quinones is proposed to account for these effects. The activation of polycyclic aromatic hydrocarbons to phenols and quinones is proposed to involve radical intermediates.
The aim of this project is to provide information on radical and quinone reactions in a biological milieu using several such systems, to include identification of radical species and elucidation of their mechanisms of formation and decay to molecular products. Studies of semiquinone and aryl(oxy) radicals, radical cations, and quinones from the enzymatic and non-enzymatic degradation of catechol(amine)s, catechol(estrogen)s, phenols and methoxy benzenes are proposed using both direct and indirect electron spin resonance methods and other appropriate techniques. Specific systems to be investigated are the following: (i) Radical (adduct) formation from tyrosinase oxidation of catechols and catecholamines in the presence of amino acids, peptides and proteins. (ii) Radical and quinone formation from tyrosinase/peroxidase-catalyzed oxidation of estrogens and catechol estrogens. Both the radical and quinone intermediates from catecholestrogens are proposed to be formed in the target organs of toxicity. (iii) Enzymatic reduction of adrenochrome to semiquinone and oxy radicals. The myocardial necrosis elicited by adrenochrome is linked to formation of toxic reduction products. (iv) Identification of radicals from the oxidation of tyrosine-containing proteins and polypeptides. (v) The enzymatic and non-enzymatic oxidation of 4-aminocatechol, a nephrotoxin related to a metabolite of the widely used analgesic drug, acetominophen. (vi) Identification of the phenoxyl radical from VP-16 and its reactions with endogenous cellular reductants. (vii) Radical cation formation from oxidation of simple methoxy-substituted benzenes and its reactions. This system is used as a model for understanding reactions of radical cation (an ultimate carcinogen) of polycyclic aromatic hydrocarbons.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM029035-07
Application #
3276488
Study Section
Physical Biochemistry Study Section (PB)
Project Start
1981-04-01
Project End
1988-07-31
Budget Start
1986-08-01
Budget End
1987-07-31
Support Year
7
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Roy, D; Kalyanaraman, B; Liehr, J G (1991) Xanthine oxidase-catalyzed reduction of estrogen quinones to semiquinones and hydroquinones. Biochem Pharmacol 42:1627-31
Kalyanaraman, B; Morehouse, K M; Mason, R P (1991) An electron paramagnetic resonance study of the interactions between the adriamycin semiquinone, hydrogen peroxide, iron-chelators, and radical scavengers. Arch Biochem Biophys 286:164-70
Kersten, P J; Kalyanaraman, B; Hammel, K E et al. (1990) Comparison of lignin peroxidase, horseradish peroxidase and laccase in the oxidation of methoxybenzenes. Biochem J 268:475-80
Kalyanaraman, B (1990) Characterization of o-semiquinone radicals in biological systems. Methods Enzymol 186:333-43
Kalyanaraman, B; Baker, J E (1990) On the detection of paramagnetic species in the adriamycin-perfused rat heart: a reappraisal. Biochem Biophys Res Commun 169:30-8
Feix, J B; Kalyanaraman, B (1989) Spin trapping of lipid-derived radicals in liposomes. Biochim Biophys Acta 992:230-5
Kalyanaraman, B; Sealy, R C; Liehr, J G (1989) Characterization of semiquinone free radicals formed from stilbene catechol estrogens. An ESR spin stabilization and spin trapping study. J Biol Chem 264:11014-9
Kalyanaraman, B; Nemec, J; Sinha, B K (1989) Characterization of free radicals produced during oxidation of etoposide (VP-16) and its catechol and quinone derivatives. An ESR Study. Biochemistry 28:4839-46
Athar, M; Mukhtar, H; Bickers, D R et al. (1989) Evidence for the metabolism of tumor promoter organic hydroperoxides into free radicals by human carcinoma skin keratinocytes: an ESR-spin trapping study. Carcinogenesis 10:1499-503
Baker, J E; Kalyanaraman, B (1989) Ischemia-induced changes in myocardial paramagnetic metabolites: implications for intracellular oxy-radical generation. FEBS Lett 244:311-4

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