MECHANISM OF CARCINOGENESIS OF DIBENZ ACRIDINE

多环芳烃(PAHs)及其氮杂类似物(aza- 多环芳烃)是普遍存在的环境致癌物质。已知多环芳烃 需要对其湾区二醇环氧化物进行代谢激活 产生致癌作用，但直到最近才有证据表明 与湾区二醇环氧化物有关的R，S，S，R绝对 作为最终致癌物的几种多环芳烃的构型包括 苯并(A)芘(BP)。然而，这件事还没有解决。 最近的研究表明，许多潜在的致癌物质 多环芳烃和氮杂多环芳烃可能在两个方面与BP不同：(I) 某些湾区二元醇环氧化物的绝对构型 多环芳烃，如二苯并(a，j)菲及其14-氮杂类似物 二苯并(c，h)吖啶，可能不会在 确定其致瘤性以及(Ii)某些多环芳烃，例如 二苯并(a，h)菲、7-甲基苯并(A)菲和7，12- 二甲基苯并(A)菲可能不会被代谢到它们各自的- 活性R，S，S，R-湾区高取代度二醇环氧化合物 立体选择性。在这两个方面，我们认为Steric 湾区空间位阻、分子水平等因素 形状和/或某些取代基(例如甲基或 Aza)扮演着重要的角色。为了更好地理解 可能影响(I)的分子因素(包括空间位阻因素) 湾区二醇的致癌和致突变活性 环氧化物对映体和(Ii)酶的立体选择性 参与多环芳烃和氮杂多环芳烃的代谢激活，我们 建议研究二苯并(a，h)吖啶DB(a，h)ACR作为模型 化合物，并将我们的结果与以前获得的结果进行比较 与其他多环芳烃和氮杂多环芳烃。Db(a，h)ACR与以前不同 研究了二苯并(c，h)-吖啶的分子形态和在 湾区的空间约束程度。 拟议研究的具体目标是：(I)综合 对映体纯的DB(a，h)ACR-10，11-二醇及其环氧化物， (2)确定新陈代谢所涉及的立体选择性 DB(a，h)ACR及其对映体纯DB(a，h)ACR-10，11-二醇的研究 DB(a，h)ACR-10，11-二醇和DB(a，h)ACR-10，11-二醇-8，9-环氧化物， 分别从对照组、3-MC处理组和PB-1组的肝微粒体中提取 用纯化和重组的细胞色素P-450c处理大鼠 系统，(三)评估诱变和致瘤活动 DB(a，h)ACR及其对映体纯二氢二醇和二醇的研究 以及(Iv)评估立体化学模型 由Jerina等人提出。细胞色素的多环芳烃结合部位 P-450C。

Polycyclic aromatic hydrocarbons (PAHs) and their aza-analogs (aza- PAHs) are ubiquitous environmental carcinogens. PAHs are known to require metabolic activation to their bay-region diol epoxides for producing their carcinogenic effects, but only recent evidence has implicated the bay-region diol epoxides with R,S,S,R absolute configuration as the ultimate carcinogens of several PAHs including benzo(a)pyrene (BP). However, the matter is not yet settled. Recent studies have indicated that many potentially carcinogenic PAHs and aza-PAHs may differ from BP in two aspects: (i) the absolute configuration of the bay-region diol epoxide of certain PAHs, such as dibenz(a,j)anthracene and its 14-aza-analog dibenz(c,h)acridine, may not play a major a major role in determining their tumorigenicity and (ii) certain PAHs, such as dibenz(a,h)anthracene, 7-methylbenz(a)anthracene and 7,12- dimethylbenz(a)anthracene may not be metabolized to their respec- tive R,S,S,R -bay-region diol epoxides with a high degree of stereoselectivity. In both the aspects, we believe that steric factors such as steric constraint in the bay-region, molecular shape and/or the presence of certain substituents (e.g. methyl or aza) play a significant role. In order to better understand the molecular factors (including steric ones) that may influence (i) the tumorigenic and mutagenic activities of the bay-region diol epoxide enantiomers, and (ii) the stereoselectivity of the enzymes involved in the metabolic activation of PAHs and aza-PAHs, we propose to study dibenz(a,h)acridine DB(a,h)ACR as a model compound, and compare our results with those obtained previously with other PAHs and aza-PAHs. DB(a,h)ACR differs from previously studied dibenz(c,h)-acridine in its molecular shape and in the degree of steric constraint in the bay-region. The specific aims of the proposed research are: (i) to synthesize enantiomerically pure DB(a,h)ACR-10,11-diols and their epoxides, (ii) to determine the stereoselectivity involved in the metabolism of DB(a,h)ACR and its enantiomerically pure DB(a,h)ACR-10,11-diols to DB(a,h)ACR-10,11-diols and DB(a,h)ACR-10,11-diol-8,9-epoxides, respectively by liver microsomes from control, 3-MC-treated and PB- treated rats, and by a purified and reconstituted cytochrome P-450c system, (iii) to assess the mutagenic and tumorigenic activities of DB(a,h)ACR and its enantiomerically pure dihydrodiol and diol epoxide derivatives, and (iv) to evaluate the stereochemical model proposed by Jerina et al. for the PAH binding site of cytochrome P-450c.