MECHANISM OF CARCINOGENESIS OF DIBENZ ACRIDINE

多环芳烃（PAHs）及其氮杂类似物（aza-analogs） 多环芳烃是普遍存在的环境致癌物。 已知多环芳烃 需要代谢活化其海湾区二醇环氧化物， 产生致癌作用，但只有最近的证据表明， 暗示海湾区二醇环氧化物与R，S，S，R绝对 作为几种多环芳烃的最终致癌物， 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） 某些海湾区域二醇环氧化物的绝对构型 多环芳烃，如二苯并（a，j）蒽及其14-氮杂-类似物 二苯并（c，h）吖啶，可能不会发挥主要作用， 确定其致瘤性和（ii）某些多环芳烃，如 二苯并（a，h）蒽、7-甲基苯并（a）蒽和7，12- 二甲基苯（a）蒽可能不会代谢成它们各自的 具有高度的环氧化度的活性R，S，S，R -海湾区二醇环氧化物， 立体选择性 在这两个方面，我们认为， 诸如在海湾区域中的空间约束、分子 形状和/或某些取代基（例如甲基或 #21453;起重要作用。 为了更好地理解 可能影响（i）的分子因素（包括空间因素） 海湾二醇的致瘤和致突变活性 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活化，我们 建议以二苯并（a，h）吖啶DB（a，h）ACR为模型化合物进行研究 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）-吖啶在其分子形状和 在海湾地区的空间限制程度。 拟议研究的具体目标是：（一）综合 对映体纯的DB（a，h）ACR-10，11-二醇及其环氧化物， (ii)以确定代谢中涉及的立体选择性 DB（a，h）ACR及其对映体纯的DB（a，h）ACR-10，11-二醇 DB（a，h）ACR-10，11-二醇和DB（a，h）ACR-10，11-二醇-8，9-环氧化物， 对照组、3-MC处理组和PB处理组的肝微粒体中， 处理的大鼠，并通过纯化和重建的细胞色素P-450 c 系统，（iii）评估致突变和致肿瘤活性 DB（a，h）ACR及其对映体纯的二氢二醇和二醇的 环氧化物衍生物，和（iv）评价立体化学模型 由Jerina等人提出，用于细胞色素的PAH结合位点 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.