Lin J M, Amin S, Trushin N, Hecht S S
Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, NY 10595.
Cancer Lett. 1993 Nov 1;74(3):151-9. doi: 10.1016/0304-3835(93)90237-4.
Previous studies have shown that benzyl isothiocyanate (BITC) inhibited lung tumorigenesis induced in A/J mice by benzo[a]pyrene (BaP), but other experiments using a somewhat different protocol demonstrated that phenethyl isothiocyanate (PEITC) had no effect on lung tumorigenesis induced by BaP in this strain. In contrast, PEITC but not BITC had been shown to inhibit lung tumorigenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice. Therefore, one goal of this study was to directly compare the chemopreventive activities of BITC and PEITC on BaP-induced lung tumorigenesis in A/J mice. In the same experiment we also compared the tumorigenic activities of BaP and NNK. Either BITC or PEITC was administered by gavage 15 min before gavage of BaP. This regimen was carried out three times at 2-week intervals, and the mice were sacrificed 26 weeks after the first treatment. As assessed by tumor multiplicity, BITC but not PEITC significantly inhibited lung tumorigenesis by BaP, whereas PEITC but not BITC significantly inhibited forestomach tumorigenesis. Comparison of the tumorigenic activities of NNK and BaP demonstrated that NNK was about ten times more potent than BaP as a lung tumorigen, while BaP but not NNK induced forestomach tumors. In a second set of experiments we evaluated the effects of isothiocyanates on the mouse skin tumor-initiating activity of BaP. The isothiocyanates tested were BITC, PEITC, 6-phenylhexyl isothiocyanate (PHITC) and a series of isothiocyanates structurally related to polynuclear aromatic hydrocarbons: 9-phenanthryl isothiocyanate (9-PhenITC), 9-phenanthrylmethyl isothiocyanate (9-PhenMeITC), 6-chrysenyl isothiocyanate (6-ChrysITC) and 6-benzo[a]pyrenyl isothiocyanate (6-BaPITC). None of the isothiocyanates inhibited tumor development by BaP, and three of them--PHITC, 9-PhenITC and 9- PhenMeITC--enhanced skin tumor multiplicity. Taken together with available literature data, the results of this study suggest that different isothiocyanates selectively inhibit cytochrome P450 enzymes involved in the metabolic activation or detoxification of BaP and therefore have differing effects on BaP tumorigenesis.
先前的研究表明，苄基异硫氰酸酯（BITC）可抑制苯并[a]芘（BaP）在A/J小鼠中诱导的肺癌发生，但其他采用略有不同实验方案的实验表明，苯乙基异硫氰酸酯（PEITC）对该品系小鼠中BaP诱导的肺癌发生没有影响。相比之下，已表明PEITC而非BITC可抑制4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）在A/J小鼠中诱导的肺癌发生。因此，本研究的一个目标是直接比较BITC和PEITC对A/J小鼠中BaP诱导的肺癌发生的化学预防活性。在同一实验中，我们还比较了BaP和NNK的致瘤活性。在灌胃BaP前15分钟通过灌胃给予BITC或PEITC。该方案每隔2周进行3次，在首次治疗后26周处死小鼠。通过肿瘤多发性评估，BITC而非PEITC显著抑制了BaP诱导的肺癌发生，而PEITC而非BITC显著抑制了前胃肿瘤发生。NNK和BaP致瘤活性的比较表明，NNK作为肺癌致癌物的效力约为BaP的10倍，而BaP而非NNK诱导了前胃肿瘤。在第二组实验中，我们评估了异硫氰酸酯对BaP诱导小鼠皮肤肿瘤起始活性的影响。所测试的异硫氰酸酯有BITC、PEITC、6-苯基己基异硫氰酸酯（PHITC）以及一系列与多环芳烃结构相关的异硫氰酸酯：9-菲基异硫氰酸酯（9-PhenITC）、9-菲甲基异硫氰酸酯（9-PhenMeITC）、6-屈基异硫氰酸酯（6-ChrysITC）和6-苯并[a]芘基异硫氰酸酯（6-BaPITC）。没有一种异硫氰酸酯抑制BaP诱导的肿瘤发展，其中三种——PHITC、9-PhenITC和9-PhenMeITC——增加了皮肤肿瘤的多发性。结合现有文献数据，本研究结果表明，不同的异硫氰酸酯选择性抑制参与BaP代谢活化或解毒的细胞色素P450酶，因此对BaP致瘤作用有不同影响。
