Reactive oxygen species (superoxide, hydrogen peroxide, and hydroxyl and peroxy radicals) are genotoxic and have been implicated in the activation of procarcinogens. The copper chelate Cu(II) (3,5-diisopropylsalicylate)2[Cu(Dips)2] is capable of detoxifying these oxygen species and can inhibit the mutagenicity and tumorigenicity of the procarcinogen DMBA. The major objectives of this proposal are: (1) to survey the effects of Cu(Dips)2 and its analogues on the mutagenicity and cytotoxicity of a variety of promutagens and direct acting mutagens; (2) determine whether Cu(Dips)2 effects are due to its oxygen scavenging properties; (3) survey the effects of a series of Cu(Dips)2 analogues that are either more or less lipophilic than the parent compound; (4) characterize the contributions of enzymes of the arachidonic acid pathway (prostaglandin endoperoxide synthetase (PES) and lipoxygenases) to promutagen metabolism in the skin, and determine whether Cu(Dips)2 inhibits these enzymes; (5) include tumor experiments to determine whether Cu(Dips)2 and its analogues can inhibit the initiation phase of two-stage chemical carcinogenesis in murine skin. Structural analogues of Cu(Dips)2 that are either more or less lipophilic than the parent compound, or lack the oxygen scavenging properties of Cu(Dips)2 will be tested with a variety of mutagens in both an Ames S. typhimurium revertant assay, and a keratinocyte cell-mediated mutation assay. The novel possibility that lipoxygenases and PES contribute to the metabolism of xenobiotics in murine skin, and that Cu(Dips)2 affects these enzymes, will be examined by determining the effects of the singular and combinational use of lipoxygenase or PES inhibitors with Cu(Dips)2 in the keratinocyte cell-mediated mutation assay, and the effects of these agents on the metabolism of hydrocarbons and the synthesis of prostaglandins and hydroperoxy fatty acids in cultured keratinocytes, and their abilities to act as anti-initiators in a murine skin two-stage carcinogenesis protocol. Effects of Cu(Dips)2 on the cyclooxygenase and peroxidase activities of PES will also be analyzed in ram seminal vesicles, a tissue that has no P-450-dependent monooxygenase activities. Copper chelates are currently in use, or are being considered for use in clinical medicine. The studies of this proposal will evaluate the chemo-preventive values of copper chelates as anti-initiators, and characterize the contributions of enzymes of the arachidonic acid pathway to xenobiotic metabolism in skin.
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