Falzon M, McMahon J B, Schuller H M, Boyd M R
Cancer Res. 1986 Jul;46(7):3484-9.
In the normal lungs of many animal species, 4-ipomeanol is transformed to a highly reactive metabolite preferentially in pulmonary bronchiolar Clara cells and to a lesser extent in alveolar type II cells, potentially leading to damage or destruction of these cell types. Since Clara cells and type II cells are suspected sites of origin of certain "non-small cell" lung cancers, the metabolic activation of 4-ipomeanol (measured by the metabolism-dependent covalent binding of 4-ipomeanol to cellular macromolecules) was compared in two human non-small cell carcinoma derived cell lines (NCI-H322 and NCI-H358) and two human small cell carcinoma derived cell lines (NCI-H128 and NCI-H69). Metabolic activation of 4-ipomeanol was evident in the non-small cell lines; the production of covalently bound metabolite was somewhat greater in NCI-H322 (morphology related to Clara cells) compared to NCI-H358 (morphology related to alveolar type II cells), but was entirely undetectable in the small cell lines. The activation pathway was concentration (4-ipomeanol) and time dependent and followed Michaelis-Menten kinetics. Metabolism to the reactive intermediate required oxygen and was strongly inhibited by carbon monoxide. Covalent binding was enhanced in the non-small cell lines by prior incubation with beta-naphthoflavone and by supplementation of the incubate with exogenous reduced nicotinamide adenine dinucleotide phosphate. 4-Ipomeanol was more cytotoxic to the non-small cell lines than to the small cell lines under the in vitro growth conditions used. These studies indicate that certain human non-small cell lung cancers have metabolic characteristics of normal bronchiolar Clara cells and alveolar type II cells; these results would therefore be consistent with an origin of these tumors from Clara cells or type II cells, respectively. The present studies indicate that the further preclinical testing and development of 4-ipomeanol is warranted, with a view toward possible clinical evaluation against human lung cancers.
在许多动物物种的正常肺组织中，4-异丙烯基苯甲醇优先在肺细支气管的克拉拉细胞中转化为一种高反应性代谢物，在肺泡II型细胞中的转化程度较低，这可能导致这些细胞类型的损伤或破坏。由于克拉拉细胞和II型细胞被怀疑是某些“非小细胞”肺癌的起源部位，因此在两种人非小细胞癌衍生细胞系（NCI-H322和NCI-H358）和两种人小细胞癌衍生细胞系（NCI-H128和NCI-H69）中比较了4-异丙烯基苯甲醇的代谢活化情况（通过4-异丙烯基苯甲醇与细胞大分子的代谢依赖性共价结合来测量）。4-异丙烯基苯甲醇的代谢活化在非小细胞系中很明显；与NCI-H358（与肺泡II型细胞形态相关）相比，NCI-H322（与克拉拉细胞形态相关）中产生的共价结合代谢物略多，但在小细胞系中完全检测不到。活化途径是浓度（4-异丙烯基苯甲醇）和时间依赖性的，并遵循米氏动力学。代谢为反应性中间体需要氧气，并受到一氧化碳的强烈抑制。通过预先用β-萘黄酮孵育以及在孵育液中补充外源性还原型烟酰胺腺嘌呤二核苷酸磷酸，非小细胞系中的共价结合增强。在所用的体外生长条件下，4-异丙烯基苯甲醇对非小细胞系的细胞毒性比对小细胞系更大。这些研究表明，某些人非小细胞肺癌具有正常细支气管克拉拉细胞和肺泡II型细胞的代谢特征；因此，这些结果分别与这些肿瘤起源于克拉拉细胞或II型细胞一致。目前的研究表明，有必要对4-异丙烯基苯甲醇进行进一步的临床前测试和开发，以期对人类肺癌进行可能的临床评估。
