Manson M M, Hudson E A, Ball H W, Barrett M C, Clark H L, Judah D J, Verschoyle R D, Neal G E
MRC Toxicology Unit, University of Leicester, UK.
Carcinogenesis. 1998 Oct;19(10):1829-36. doi: 10.1093/carcin/19.10.1829.
Indole-3-carbinol (I3C) was examined for its ability to inhibit aflatoxin B1 (AFB1)-induced hepatocarcinogenesis in male Fischer rats when administered either before or after the carcinogen. After 13 weeks, animals pretreated with I3C (0.5% in the diet) for 2 weeks prior to administration of AFB1 and with continuing treatment during exposure to the carcinogen were protected from development of preneoplastic lesions, as determined by the classical markers gamma-glutamyltranspeptidase (GGT) and glutathione S-transferase (GST) P. In animals receiving AFB1 for 6 weeks before treatment with I3C, there was no obvious protective effect at 13 weeks compared with animals receiving only AFB1. Using cytokeratin 18 expression as a marker, animals fed AFB1 alone had a small number of positive foci at 13 weeks. However, no cytokeratin-positive foci were visible in the majority of livers from either group receiving I3C in combination with AFB1 and after 43 weeks all animals in these groups were protected from liver tumour formation. These results suggest that expression of cytokeratin 18, a later phenotypic change in foci than induction of GST-P and GGT, correlates more closely with tumour outcome in this model. I3C appeared to retard progression of AFB1-induced carcinogenesis at both the initiation and promotion stages. Continuous treatment with I3C for 13 weeks caused significant induction of CYP1A1, 1A2, 3A and 2B1/2, GST Yc2, aflatoxin B1 aldehyde reductase and quinone reductase. Such alteration of the drug metabolizing capacity of the liver by I3C contributes to blocking of initiation, while the observed inhibition of ornithine decarboxylase, a rate limiting enzyme in polyamine biosynthesis, and of tyrosine kinase activity may contribute to the suppressive effect of I3C.
研究了吲哚 - 3 - 甲醇（I3C）在致癌物黄曲霉毒素B1（AFB1）之前或之后给药时，抑制雄性Fischer大鼠AFB1诱导的肝癌发生的能力。13周后，在给予AFB1前2周用I3C（饮食中含0.5%）预处理并在接触致癌物期间持续治疗的动物，通过经典标志物γ - 谷氨酰转肽酶（GGT）和谷胱甘肽S - 转移酶（GST）P测定，可免受癌前病变的发展。在用I3C治疗前接受AFB1 6周的动物中，与仅接受AFB1的动物相比，在13周时没有明显的保护作用。以细胞角蛋白18表达为标志物，单独喂食AFB1的动物在13周时有少量阳性灶。然而，在接受I3C与AFB1联合治疗的两组大多数肝脏中，未观察到细胞角蛋白阳性灶，并且在43周后这些组中的所有动物都免受肝肿瘤形成。这些结果表明，细胞角蛋白18的表达作为病灶中比GST - P和GGT诱导更晚的表型变化，在该模型中与肿瘤结局更密切相关。I3C似乎在起始和促进阶段均延缓了AFB1诱导的致癌作用进展。用I3C连续治疗13周导致CYP1A1、1A2、3A和2B1/2、GST Yc2、黄曲霉毒素B1醛还原酶和醌还原酶的显著诱导。I3C对肝脏药物代谢能力的这种改变有助于阻断起始过程，而观察到的对鸟氨酸脱羧酶（多胺生物合成中的限速酶）和酪氨酸激酶活性的抑制可能有助于I3C的抑制作用。
