Complete inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced rat lung tumorigenesis and favorable modification of biomarkers by phenethyl isothiocyanate.
Complete inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced rat lung tumorigenesis and favorable modification of biomarkers by phenethyl isothiocyanate.
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发表时间：
1996-08
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通讯作者：
S. Hecht;N. Trushin;J. Rigotty;S. Carmella;A. Borukhova;S. Akerkar;A. Rivenson
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作者：
S. Hecht;N. Trushin;J. Rigotty;S. Carmella;A. Borukhova;S. Akerkar;A. Rivenson
异硫氰酸苯乙酯(PEITC)存在于某些十字花科蔬菜中，在一项几乎终身服用这两种化合物的研究中，测试了其抑制烟草特有的亚硝胺4-(甲基亚硝氨基-1-(3-吡啶)-1-丁酮(NNK)诱发大鼠肺部肿瘤的能力。此外，在随机选择的大鼠中，对NNK代谢的两个生物标志物[4-羟基-1-(3-吡啶)-1-丁酮加合物]和4-(尿中的甲基亚硝基-1-3-吡啶-1-丁醇及其葡萄糖醛酸化物)进行了定量。将大鼠分为：NNK组，饮水2ppm，60只；NNK，饮用水和PEITC，2ppm，3微克/g NIH-07饲料组，60只；PEITC，3微克/g NIH-07饲料组，20只；未处理对照组，20只。在给予NNK之前，在饮用水中加入NNK 111周，在饮食中加入PEITC 1周，然后在整个111周的疗程中加入NNK。在体重或存活率方面，两组之间没有显著差异。PEITC对血液化学或血液学无明显影响。NNK可诱发70%的大鼠肺肿瘤(腺瘤和/或腺癌)。在NNK+PEITC治疗组中，5%的大鼠发生了肺肿瘤，与对照组相比差异无统计学意义。PEITC似乎还能抑制胰腺肿瘤从良性向恶性的发展。在研究期间，每隔一段时间从选定的大鼠中抽取血液，并对NNK代谢激活时形成的4-羟基-1-(3-吡啶)-1-丁酮加合物进行定量。在整个研究过程中，与NNK治疗的大鼠相比，NNK联合PEITC治疗的大鼠的血红蛋白加合物显著受到抑制。对几只大鼠的24小时尿样进行了4-(甲基亚硝基)-1-(3-吡啶)-1-丁醇和4-(甲基亚硝基)-1-(3-吡啶)-1-丁醇葡萄糖醛酸苷的分析。在NNK加PEITC治疗的大鼠中，观察到这些代谢物的总和比NNK治疗的大鼠增加了4-6倍。这也与PEITC对NNK代谢激活的抑制作用一致。总而言之，这项研究的结果提供了强有力的证据，证明了PEITC作为一种化学预防药物对NNK诱导的大鼠肺癌的有效性，并表明在烟草消费者中可以测量到的NNK代谢的两个生物标记物可以通过PEITC给药以可预测的方式进行调节。
Phenethyl isothiocyanate (PEITC), which occurs in certain cruciferous vegetables, was tested for its ability to inhibit lung tumorigenesis in rats induced by the tobacco-specific nitrosamine 4-(methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in a study involving virtually lifelong administration of both compounds. In addition, two biomarkers of NNK metabolism [4-hydroxy-1-(3-pyridyl)-1-butanone-releasing hemoglobin adducts and 4-(methylnitrosamino-1-3-pyridyl-1-butanol and its glucuronide in urine] were quantified in randomly selected rats during the course of the study. The rats were assigned to groups as follows: NNK, 2 ppm in drinking water, 60 rats; NNK, 2 ppm in drinking water and PEITC, 3 micromol/g NIH-07 diet, 60 rats; PEITC, 3 micromol/g NIH-07 diet, 20 rats; and untreated controls, 20 rats. NNK was added to the drinking water for 111 weeks and PEITC to the diet for 1 prior to NNK administration and then throughout the 111-week course of treatment. There were no significant differences in body weights or survival among the groups. There were no significant effects of PEITC on blood chemistry or hematology. NNK induced lung tumors (adenoma and/or adenocarcinoma) in 70% of the rats. In the group treated with NNK plus PEITC, 5% of the rats had lung tumors, which was not different from that of control rats. PEITC also appeared to inhibit progression of benign to malignant pancreatic tumors. At intervals during the study, blood was withdrawn from selected rats, and 4-hydroxy-1-(3-pyridyl)-1-butanone-releasing hemoglobin adducts, which are formed upon metabolic activation of NNK, were quantified. The hemoglobin adducts were significantly repressed throughout the study in the rats treated with NNK plus PEITC compared to those treated with NNK. The 24-h urine sample of several rats was analyzed for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol glucuronide. A 4-6-fold increase in the sum of these metabolites was observed in the rats treated with NNK plus PEITC compared to those treated with NNK. This is also consistent with inhibition of metabolic activation of NNK by PEITC. Collectively, the results of this study provide strong evidence for the efficacy of PEITC as a chemopreventive agent against NNK-induced pulmonary carcinogenesis in rats and indicate that two biomarkers of NNK metabolism, measurable in tobacco consumers, can be modulated in a predictable way by PEITC administration.