MECHANISM OF CARCINOGENESIS OF DIBENZ ACRIDINE

二苯吖啶的致癌机制

• 批准号: 3250572
• 负责人: SUBODH KUMAR
• 金额: $ 12.04万
• 依托单位: BUFFALO STATE COLLEGE
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-08-01 至 1992-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3250572
• 关键词: acridines; benzanthracenes; chemical carcinogenesis; chemical synthesis; cytochrome P450; diol; epoxides; laboratory rat; liver metabolism; microsomes; mutagens; stereochemistry

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.

多环芳烃 (PAH) 及其氮杂类似物 (氮杂- PAHs）是普遍存在的环境致癌物。 PAH 已知 需要对其湾区二醇环氧化物进行代谢激活 产生致癌作用，但只有最近的证据表明 涉及湾区二醇环氧化物与 R,S,S,R 绝对值 配置为多种多环芳烃的最终致癌物，包括 苯并(a)芘 (BP)。 然而，事情尚未解决。 最近的研究表明，许多潜在的致癌物质 PAH 和氮杂 PAH 可能在两个方面与 BP 不同：(i) 某些湾区二醇环氧化物的绝对构型 PAH，例如二苯并(a,j)蒽及其 14-氮杂类似物 二苯(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，例如 二苯并(a,h)蒽、7-甲基苯并(a)蒽和7,12- 二甲基苯并(a)蒽可能不会代谢至其各自的状态 活性R,S,S,R-湾区二醇环氧化物，具有高度 立体选择性。 在这两个方面，我们相信空间 湾区的空间约束、分子等因素 形状和/或某些取代基的存在（例如甲基或 aza）发挥着重要作用。 为了更好地了解 可能影响 (i) 的分子因素（包括空间因素） 湾区二醇的致瘤和致突变活性 环氧化物对映体，以及 (ii) 酶的立体选择性 参与 PAH 和氮杂 PAH 的代谢激活，我们 提议研究二苯并(a,h)吖啶DB(a,h)ACR作为模型 化合物，并将我们的结果与之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 与之前不同 研究了二苯并(c,h)-吖啶的分子形状和 海湾地区的空间约束程度。 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， (ii) 确定代谢中涉及的立体选择性 DB(a,h)ACR 及其对映体纯 DB(a,h)ACR-10,11-二醇 至 DB(a,h)ACR-10,11-二醇和 DB(a,h)ACR-10,11-二醇-8,9-环氧化物， 分别通过对照、3-MC处理和PB-处理的肝微粒体 治疗大鼠，并通过纯化和重构的细胞色素 P-450c 系统，(iii) 评估诱变和致瘤活性 DB(a,h)ACR 及其对映体纯的二氢二醇和二醇 环氧化物衍生物，以及（iv）评估立体化学模型 由杰琳娜等人提出。细胞色素的 PAH 结合位点 P-450c。