Chung F L, Wang M Y, Hecht S S
Carcinogenesis. 1985 Apr;6(4):539-43. doi: 10.1093/carcin/6.4.539.
Dietary-related indoles, isothiocyanates, and the allyl isothiocyanate glucosinolate, sinigrin, were administered to F344 rats in the diet for 2 weeks (chronic protocol) or by gavage 2 h before sacrifice (acute protocol) and the effects of these pretreatments on the alpha-hydroxylation of two carcinogenic nitrosamines, N-nitrosodimethylamine (NDMA) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), were evaluated. alpha-Hydroxylation was measured in vitro by quantitation of formaldehyde formation upon incubation of the nitrosamines with liver microsomes, and in vivo by quantitation of levels of 7-methylguanine and O6-methylguanine in hepatic DNA, 4 h after nitrosamine treatment. Compounds shown to be inhibitory in the in vitro assay were selected to be further evaluated using the in vivo assay. The results of the in vitro assays showed that indoles were inducers of the demethylation of both nitrosamines. Indole, L-tryptophan and indole-3-carbinol were strong inducers of NDMA and NNK demethylation, respectively. In contrast, isothiocyanates such as phenethyl isothiocyanate and phenyl isothiocyanate demonstrated a wide range of inhibitory activities toward demethylation of these nitrosamines in both the acute and chronic studies. Chronic, but not acute, pretreatment with sinigrin also caused a significant decrease in the demethylation of NDMA and NNK. In view of their promising inhibitory activities, the effects of phenethyl isothiocyanate, phenyl isothiocyanate and sinigrin on the in vivo methylation of DNA by NDMA and NNK were evaluated. The results were parallel to those obtained in the in vitro assays. Phenethyl isothiocyanate, phenyl isothiocyanate and sinigrin generally inhibited the formation of 7-methylguanine and O6-methylguanine in rat hepatic DNA. The results of this study suggest that these compounds could be anticarcinogenic to NDMA and NNK.
将与饮食相关的吲哚、异硫氰酸酯以及烯丙基异硫氰酸酯硫代葡萄糖苷（黑芥子硫苷酸钾）通过饮食给予F344大鼠2周（慢性方案），或在处死前2小时通过灌胃给予（急性方案），并评估这些预处理对两种致癌亚硝胺——N-亚硝基二甲胺（NDMA）和4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮（NNK）——α-羟基化的影响。通过在亚硝胺与肝微粒体孵育时定量甲醛生成来体外测量α-羟基化，在亚硝胺处理4小时后通过定量肝DNA中7-甲基鸟嘌呤和O6-甲基鸟嘌呤的水平来体内测量α-羟基化。选择在体外试验中显示有抑制作用的化合物，使用体内试验进一步评估。体外试验结果表明，吲哚是两种亚硝胺去甲基化的诱导剂。吲哚、L-色氨酸和吲哚-3-甲醇分别是NDMA和NNK去甲基化的强诱导剂。相比之下，异硫氰酸酯如苯乙基异硫氰酸酯和苯基异硫氰酸酯在急性和慢性研究中均对这些亚硝胺的去甲基化表现出广泛抑制活性。用黑芥子硫苷酸钾进行慢性而非急性预处理也导致NDMA和NNK去甲基化显著降低。鉴于它们有前景的抑制活性，评估了苯乙基异硫氰酸酯、苯基异硫氰酸酯和黑芥子硫苷酸钾对NDMA和NNK在体内使DNA甲基化的影响。结果与体外试验所得结果一致。苯乙基异硫氰酸酯、苯基异硫氰酸酯和黑芥子硫苷酸钾通常抑制大鼠肝DNA中7-甲基鸟嘌呤和O6-甲基鸟嘌呤的形成。本研究结果表明，这些化合物可能对NDMA和NNK具有抗癌作用。
