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.
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