Jiao D, Smith T J, Kim S, Yang C S, Desai D, Amin S, Chung F L
Division of Chemical Carcinogenesis, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, NY 10595, USA.
Carcinogenesis. 1996 Apr;17(4):755-9. doi: 10.1093/carcin/17.4.755.
The importance of the isothiocyanate group in alkyl isothiocyanate for inhibition of tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone (NNK)-induce lung tumorigenesis was examined in A/J mice. Our previous structure-activity relationship study of isothiocyanates showed that 1-dodecyl isothiocyanate [CH3(CH2)11NCS], a simple alkyl isothiocyanate, is a potent inhibitor of NNK-induced lung tumorigenesis. It was chosen for this study due to its structural features and potency. A single dose of 1-dodecyl isothiocyanate given by gavage at 1 micromol/mouse 2 h prior to NNK administration completely inhibited lung tumorigenesis, while removal of the isothiocyanate group or replacing it with a hydroxyl group abolished the inhibitory activity. These results demonstrate that the isothiocyanate functional group is critical for the inhibitory activity of isothiocyanates in NNK-induced lung tumorigenesis. To gain more insights into the relationship of in vivo inhibition of tumorigenesis with the cytochrome P-450 enzyme inhibitory activity, the effects of these compounds on metabolism of NNK in mouse lung microsomes were studied. 1-Dodecyl isothiocyanate inhibited all three known oxidative pathways of NNK metabolism, with a stronger inhibitory activity toward NNK N-oxidation (IC50 430 nM) and keto alcohol formation (IC50 500 nM) than keto aldehyde formation (IC50 13,000 nM). 1-Dodecanol had a similar selectivity in inhibition of these metabolic pathways, but was less potent than 1-dodecyl isothiocyanate. Dodecane showed little or no inhibitory activity in the same concentration range. These results indicate that the isothiocyanate group of 1-dodecyl isothiocyanate is important for inhibition of NNK-induced lung tumorigenesis and also for effective inhibition of cytochrome P-450 enzymes involved in NNK oxidation.
在A/J小鼠中研究了异硫氰酸酯基团在烷基异硫氰酸酯中对抑制烟草特异性亚硝胺4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮(NNK)诱导的肺肿瘤发生的重要性。我们之前关于异硫氰酸酯的构效关系研究表明，1-十二烷基异硫氰酸酯[CH3(CH2)11NCS]，一种简单的烷基异硫氰酸酯，是NNK诱导的肺肿瘤发生的有效抑制剂。由于其结构特点和效力，它被选用于本研究。在给予NNK前2小时，以1微摩尔/小鼠的剂量经口灌胃给予1-十二烷基异硫氰酸酯，可完全抑制肺肿瘤发生，而去除异硫氰酸酯基团或用羟基取代它则消除了抑制活性。这些结果表明，异硫氰酸酯官能团对于异硫氰酸酯在NNK诱导的肺肿瘤发生中的抑制活性至关重要。为了更深入了解体内肿瘤发生抑制与细胞色素P-450酶抑制活性之间的关系，研究了这些化合物对小鼠肺微粒体中NNK代谢的影响。1-十二烷基异硫氰酸酯抑制NNK代谢的所有三种已知氧化途径，对NNK N-氧化(IC50 430 nM)和酮醇形成(IC50 500 nM)的抑制活性比对酮醛形成(IC50 13,000 nM)更强。1-十二烷醇在抑制这些代谢途径方面具有类似的选择性，但效力低于1-十二烷基异硫氰酸酯。十二烷在相同浓度范围内几乎没有或没有抑制活性。这些结果表明，1-十二烷基异硫氰酸酯的异硫氰酸酯基团对于抑制NNK诱导的肺肿瘤发生以及有效抑制参与NNK氧化的细胞色素P-450酶很重要。
