ENVIRONMENTAL COCARCINOGENS--FLUORANTHENE AND PYRENE

荧蒽和芘，在整个人类环境中发现。 这些 多环芳烃（PAH）与 苯并[a]芘（BaP）主要是由有机物的不完全燃烧产生的。 几项研究表明，荧蒽和芘发挥了 对BaP有致癌作用，但两种化合物均无肿瘤活性 启动子 我们的实验室已经证明，荧蒽和 芘，当与BaP一起应用于小鼠皮肤时， 与单独的BaP相比，BaP-DNA加合物形成水平增加。 的 该提案的目的是确定这一点的分子基础 观察. 荧蒽和芘对苯并（a）芘体内代谢的影响 将测定小鼠皮肤。 这些研究将解决以下问题： 共致癌物是否诱导小鼠皮肤中BaP的代谢活化 或竞争解毒途径。 荧蒽的代谢和 还将对小鼠皮肤中的芘进行体内研究。 主要代谢产物将 评价它们对体内BaP-DNA加合物形成的影响 在老鼠的皮肤上。 这些相同的代谢物对体内 还将测定BaP在小鼠皮肤中的代谢。 的可能性 荧蒽和芘的亲电代谢物可以与小鼠结合， 将评估皮肤DNA、RNA和蛋白质。 荧蒽的甲基化 和芘，导致BaP-DNA加合物形成增加， 发现与细胞大分子结合的亲电代谢物将被 在小鼠皮肤上测定共致癌性。

Fluoranthene and pyrene and found throughout the human environment. These polycyclic aromatic hydrocarbons (PAH) are formed together with benzo[a]pyrene (BaP) primarily by incomplete combustion of organic matter. Several studies have demonstrated that fluoranthene and pyrene exert a cocarcinogenic effect on BaP although neither compound is active as a tumor promoter. It has been demonstrated in our laboratory that fluoranthene and pyrene, when applied together with BaP in vivo in mouse skin, lead to increased levels of BaP-DNA adduct formation as compared to BaP alone. The objective of this proposal is to determine the molecular basis for this observation. The effect of fluoranthene and pyrene on the in vivo metabolism of BaP in mouse skin will be determined. These studies will address the question of whether the cocarcinogens induce metabolic activation of BaP in mouse skin or compete for detoxification pathways. The metabolism of fluoranthene and pyrene in vivo in mouse skin will also be studied. Major metabolites will be evaluated for their effect on the in vivo formation of BaP-DNA adducts in mouse skin. The effects of these same metabolites on the in vivo metabolism of BaP in mouse skin will also be determined. The possibility that electrophilic metabolites of fluoranthene and pyrene can bind to mouse skin DNA, RNA, and proteins will be evaluated. Metabolites of fluoranthene and pyrene which lead to increased BaP-DNA adduct formation and electrophilic metabolites found to bind to cellular macromolecules will be assayed for cocarcinogenicity on mouse skin.