IPOMEANOL ANALOGUES AND NNK LUNG TUMORIGENESIS

4-异丙醇(IPO)是一种新陈代谢的强效肺毒素。 在肺的Clara细胞中被细胞色素P450酶激活。4- 甲基亚硝氨基-1-(3-吡啶)-1-丁酮(NNK)是烟草特有的 亚硝胺是一种强烈的肺癌致癌物，也是 在Clara细胞中被细胞色素P450酶代谢激活。它 被认为在烟草引起的肺癌中起着重要作用。这个 IPO和NNK的结构相似。我们的假设是无毒的 IPO的结构类似物可能是NNK的竞争性抑制物 在肺中的代谢激活，因此可以抑制其 致瘤性。我们的初步结果表明，这是 凯斯。我们建议把初步研究范围扩大至以下范围： 1.合成14C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-硫苯基)-1- 戊酮(HTP)。而这三种化合物都抑制NNK 肺微粒体的体外代谢，仅HPP和HPO 抑制NNK致瘤性。我们将研究新陈代谢和 [14C]HPP、HPO和HTP在A/J小鼠体内的分布 抑制NNK致瘤性的机制研究。 2.确定IPO类似物对形成和 O6-甲基鸟嘌呤在A/J小鼠肺组织中的持久性 和NNK在一起。这种错误编码的DNA加合物在NNK中是至关重要的 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 活体作为NNK代谢激活的抑制剂。执行 NNK抑制剂类化合物的生物测定 肿瘤发生学。这些有希望的类似物也将被合成 以有标签的形式。 4.测定IPO及其类似物抑制NNK的能力 在Clara细胞和其他肺细胞类型中的代谢，以及在 从转导编码基因的细胞中制备微生物体 人细胞色素P450。检查标记物的新陈代谢 这些系统中的类似物。 这项研究的结果将为新机制的开发提供指导 NNK肿瘤发生的基础抑制剂，并将加深我们的理解 与有效新陈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.