Chaumontet C, Suschetet M, Honikman-Leban E, Krutovskikh V A, Berges R, Le Bon A M, Heberden C, Shahin M M, Yamasaki H, Martel P
Institut National de la Recherche Agronomique, Laboratoire de Nutrition et Sécurité Alimentaire, Jouy-en-Josas, France.
Nutr Cancer. 1996;26(3):251-63. doi: 10.1080/01635589609514482.
Possible tumor-promoting activity of four flavonoids, quercetin (QC), tangeretin (TG), flavone (FO), and flavanone (FN), was examined in a rat liver short-term carcinogenesis assay as well as with in vivo and in vitro assays of inhibition of gap junctional intercellular communication (GJIC). Rat hepatocarcinogenesis was induced by aflatoxin B1 treatment followed by a selection phase (2-acetylaminofluorene treatment and partial hepatectomy), then treatment with or without test chemicals (in vivo studies of antipromotion were not performed). Using glutathione S-transferase placental form (GST-P)-positive foci, we compared the effects of flavonoids (at 1,000 ppm in the diet) with the effects of phenobarbital (PB) on the occurrence of liver preneoplastic lesions. In addition, we studied the effects of flavonoids on GJIC in the livers derived from these experiments and in two types of cultured cells. No significant difference in the number and area of GST-P-positive foci was found after one or three months of treatment between any flavonoid group and control group. In the positive control group, PB markedly increased the numbers and areas of preneoplastic lesions at three months. Whereas PB also decreased by 60% the average size of lucifer yellow dye spread in slices of liver parenchyma free of preneoplastic lesions among the different flavonoids, only TG decreased the dye transfer in vivo: by 30% at one month and 50% at three months. With the dye transfer assay applied to a rat liver epithelial cell line (REL) and the Chinese hamster V79 metabolic cooperation assay, none of the tested flavonoids (< or = 25 microM) inhibited GJIC. Conversely, protective properties were seen for some of the compounds in antipromotion in vitro studies, because TG and FN enhanced the dye transfer in REL cells and FO, TG, and QC partly prevented the inhibition of metabolic cooperation by 12-O-tetradecanoylphorbol-13-acetate. Thus, taken together, our results suggest that QC, FO, and FN do not show tumor-promoting activity. Concerning TG, some discrepancies in the in vivo data are observed. Some of them (GJIC inhibition in liver slices) are probably more relevant to promotion of hepatocarcinogenesis.
在大鼠肝脏短期致癌试验以及体内和体外间隙连接细胞间通讯（GJIC）抑制试验中，检测了四种黄酮类化合物槲皮素（QC）、橘皮素（TG）、黄酮（FO）和黄烷酮（FN）可能的促肿瘤活性。用黄曲霉毒素B1处理诱导大鼠肝癌发生，随后进入选择阶段（2-乙酰氨基芴处理和部分肝切除术），然后用或不用受试化学物质进行处理（未进行体内抗促癌研究）。利用谷胱甘肽S-转移酶胎盘形式（GST-P）阳性灶，我们比较了黄酮类化合物（在饮食中浓度为1000 ppm）与苯巴比妥（PB）对肝脏癌前病变发生的影响。此外，我们研究了黄酮类化合物对这些实验中获取的肝脏以及两种培养细胞中GJIC的影响。在任何黄酮类化合物组与对照组之间，处理1个月或3个月后，GST-P阳性灶的数量和面积均未发现显著差异。在阳性对照组中，PB在3个月时显著增加了癌前病变的数量和面积。虽然PB也使在不含癌前病变的肝实质切片中荧光素黄染料扩散的平均大小在不同黄酮类化合物中降低了60%，但只有TG在体内降低了染料转移：1个月时降低30%，3个月时降低50%。应用于大鼠肝上皮细胞系（REL）的染料转移试验和中国仓鼠V79代谢协同试验中，所测试的黄酮类化合物（≤25 microM）均未抑制GJIC。相反，在体外抗促癌研究中，一些化合物表现出保护特性，因为TG和FN增强了REL细胞中的染料转移，并且FO、TG和QC部分地阻止了12-O-十四酰佛波醇-13-乙酸酯对代谢协同的抑制。因此，综合来看，我们的结果表明QC、FO和FN不显示促肿瘤活性。关于TG，在体内数据中观察到一些差异。其中一些（肝切片中GJIC抑制）可能与肝癌发生的促进更相关。
