de Moura Espíndola Roseli, Mazzantini Rogério Pietro, Ong Thomas Prates, de Conti Aline, Heidor Renato, Moreno Fernando Salvador
Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Carcinogenesis. 2005 Jun;26(6):1091-9. doi: 10.1093/carcin/bgi047. Epub 2005 Feb 17.
Chemopreventive activities of the isoprenoids geranylgeraniol (GGO) and beta-ionone (BI) were evaluated during initial phases of hepatocarcinogenesis. Rats received 8 or 16 mg/100 g body wt GGO (GGO8 and GGO16 groups) or BI (BI8 and BI16 groups), or only corn oil (CO group, controls) daily for 7 weeks. Incidence (%) and the mean number of visible hepatocyte nodules/animal were inhibited in the GGO8 (64% and 21 +/- 40), GGO16 (33% and 3 +/- 5), BI8 (50% and 13 +/- 34) and BI16 (42% and 9 +/- 19) groups compared with the CO group (100% and 34 +/- 51) (P < 0.05, except for the GGO8 group). Number/cm(2) liver section, mean area (mm(2)) and % liver section area occupied by persistent hepatic placental glutathione S-transferase positive preneoplastic lesions (PNL) were reduced in the GGO8 (11 +/- 9; 0.26 +/- 0.35; 2.7 +/- 3.0), GGO16 (6 +/- 6; 0.18 +/- 0.16; 0.9 +/- 0.9), BI8 (9 +/- 5; 0.13 +/- 0.20; 1.1 +/- 1.2) and BI16 (8 +/- 6; 0.08 +/- 0.09; 0.6 +/- 0.4) groups compared with the CO group (26 +/- 18; 0.29 +/- 0.34; 7.0 +/- 5.5) (P < 0.05). GGO16 and BI16 groups showed smaller visible hepatocyte nodules, reduced PNL cell proliferation and total plasma cholesterol levels compared with the CO group (P < 0.05), but did not show any differences (P > 0.05) in PNL apoptosis. DNA damage expressed as comet length (microm) was reduced in the GGO8 (96.7 +/- 1.5), GGO16 (94.2 +/- 1.5), BI8 (97.1 +/- 1.1) and BI16 (95.1 +/- 1.5) groups compared with the CO group (102.1 +/- 1.7) (P < 0.05). In comparison with normal animals, the CO group animals showed increased (P < 0.05) nuclear levels of nuclear factor kappa B (NF-kappaB) p65 subunit in hepatic cells, which were decreased (P < 0.05) in the GGO16 group animals. Anticarcinogenic actions of these isoprenoids seem to follow a dose-response relationship. Results indicate that GGO and BI could be represented as promising chemopreventive agents against hepatocarcinogenesis. Inhibition of cell proliferation and DNA damage seems to be important for the anticarcinogenic actions of isoprenoids, while the inhibition of NF-kappaB activation seems to be specifically related to GGO actions.
在肝癌发生的初始阶段，对类异戊二烯香叶基香叶醇（GGO）和β-紫罗兰酮（BI）的化学预防活性进行了评估。大鼠每天接受8或16mg/100g体重的GGO（GGO8和GGO16组）或BI（BI8和BI16组），或仅接受玉米油（CO组，对照组），持续7周。与CO组（100%和34±51）相比，GGO8（64%和21±40）、GGO16（33%和3±5）、BI8（50%和13±34）和BI16（42%和9±19）组的发生率（%）和每只动物可见肝细胞结节的平均数受到抑制（除GGO8组外，P<0.05）。与CO组（26±18；0.29±0.34；7.0±5.5）相比，GGO8（11±9；0.26±0.35；2.7±3.0）、GGO16（6±6；0.18±0.16；0.9±0.9）、BI8（9±5；0.13±0.20；1.1±1.2）和BI16（8±6；0.08±0.09；0.6±0.4）组每平方厘米肝脏切片的数量、平均面积（平方毫米）以及持续性肝胎盘谷胱甘肽S-转移酶阳性癌前病变（PNL）所占肝脏切片面积的百分比均降低（P<0.05）。与CO组相比，GGO16和BI16组可见较小的肝细胞结节，PNL细胞增殖和血浆总胆固醇水平降低（P<0.05），但在PNL凋亡方面未显示任何差异（P>0.05）。以彗星长度（微米）表示的DNA损伤在GGO8（96.7±1.5）、GGO16（94.2±1.5）、BI8（97.1±1.1）和BI16（95.1±1.5）组中比CO组（102.1±1.7）降低（P<0.05）。与正常动物相比，CO组动物肝细胞中核因子κB（NF-κB）p65亚基的核水平升高（P<0.05），而在GGO16组动物中降低（P<0.05）。这些类异戊二烯的抗癌作用似乎遵循剂量反应关系。结果表明，GGO和BI可被视为有前景的抗肝癌化学预防剂。细胞增殖和DNA损伤的抑制似乎对类异戊二烯的抗癌作用很重要，而NF-κB激活的抑制似乎与GGO的作用特别相关。
