IPOMEANOL ANALOGS AND NNK LUNG TUMORIGENESIS

4-异炔雌醇（IPO）是一种强有力的肺毒素， 由肺的Clara细胞中的细胞色素P450酶激活。 4- 甲基亚硝胺基-1-（3-吡啶基）-1-丁酮（NNK）是烟草特异性的 亚硝胺是一种强有力的肺部致癌物质， 在Clara细胞中由细胞色素P450酶代谢活化。 它 被认为在烟草诱发的肺癌中很重要。 的 IPO和NNK的结构相似。 我们的假设是， IPO的结构类似物可能是NNK的竞争性抑制剂 代谢活化，因此可以抑制其 致瘤性 我们的初步结果表明，这是 案子 我们建议将初步研究的范围扩大如下： 1. 合成14 C标记的4-羟基-1-苯基-1-戊酮（HPP）、7- 羟基-1-苯基-1-辛酮（HPO）和4-羟基-1-（2-噻吩基）-1- 戊酮（HTP）。 虽然所有三种化合物都抑制NNK 肺微粒体体外代谢，仅HPP和HPO 抑制NNK致瘤性。 我们将研究新陈代谢， [14 C]HPP、HPO和HTP在A/J小鼠中的分布，以获得了解 抑制NNK致瘤性的机制。 2. 确定IPO类似物对形成的影响， O 6-甲基鸟嘌呤在A/J小鼠肺中的持久性 关于NNK 这种错误编码的DNA加合物在NNK中至关重要 A/J小鼠的肿瘤发生。 3. 合成IPO的其他类似物并在体外和体内进行测试 作为NNK代谢活化的抑制剂。 开展 作为NNK抑制剂的有希望的类似物的生物测定 肿瘤发生 这些有前途的类似物也将被合成 以标记的形式。 4. 测定IPO及其类似物抑制NNK的能力 Clara细胞和其他肺细胞类型中的代谢，以及 从用编码以下的cDNA转染的细胞制备的微粒体： 人细胞色素P450。 检查标记的代谢 这些系统中的类似物。 本文的研究成果将为新机制的开发提供指导 基于NNK肿瘤发生的抑制剂，并将进一步我们的理解 与有效代谢相关的结构特征， 细胞色素P450酶存在于肺中。

4-Ipomeanol (IPO) is a potent pulmonary toxin which is metabolically activated by cytochrome P450 enzymes in Clara cells of the lung. 4- Methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific nitrosamine which is a potent pulmonary carcinogen and is also metabolically activated by cytochrome P450 enzymes in Clara cells. It is believed to be important in tobacco-induced lung cancer. The structures of IPO and NNK are similar. Our hypothesis is that non-toxic structural analogues of IPO could be competitive inhibitors of NNK metabolic activation in the lung and could therefore inhibit its tumorigenicity. Our preliminary results demonstrate that this is the case. We propose to extend our preliminary studies as follows: 1. Synthesize 14C-labelled 4-hydroxy-1-phenyl-1-pentanone (HPP), 7- hydroxy-1-phenyl-1-octanone (HPO) and 4-hydroxy-1-(2-thiophenyl)-1- pentanone (HTP). While all three compounds inhibited NNK metabolism in vitro by pulmonary microsomes, only HPP and HPO inhibited NNK tumorigenicity. We will study the metabolism and distribution of [14C]HPP, HPO, and HTP in A/J mice to gain insights on the mechanism of inhibition of NNK tumorigenicity. 2. Determine the effects of the IPO analogues on the formation and persistence of O6-methylguanine in the lung of A/J mice treated with NNK. This miscoding DNA adduct is critical in NNK tumorigenesis in A/J mice. 3. Synthesize other analogues of IPO and test them in vitro and in vivo as inhibitors of NNK metabolic activation. Carry out bioassays of the promising analogues as inhibitors of NNK tumorigenesis. These promising analogues will also be synthesized in labelled form. 4. Determine the ability of IPO and its analogues to inhibit NNK metabolism in Clara cells and other pulmonary cell types, and in microsomes prepared from cells transfected with cDNAs encoding human cytochromes P450. Examine the metabolism of the labelled analogues in these systems. The results of this study will lead to the development of new mechanism based inhibitors of NNK tumorigenesis and will further our understanding of the structural features associated with effective metabolism by cytochrome P450 enzymes present in the lung.