Chakraborty Tridib, Swamy A H M Viswanatha, Chatterjee Amrita, Rana Basabi, Shyamsundar A, Chatterjee Malay
Division of Biochemistry, Department of Pharmaceutical Technology, Jadavpur University, PO Box 17028, Calcutta-700032, West-Bengal, India.
J Cell Biochem. 2007 May 1;101(1):244-58. doi: 10.1002/jcb.21169.
Carcinogen-induced early DNA lesions and metallothionein (MT) over-expression have been implicated in cell proliferation and thereby subsequent expression of premalignant phenotype of the cell. We have therefore investigated the chemopreventive potential of vanadium in a multi-biomarker approach, viz. 8-hydroxy-2'-deoxyguanosines (8-OHdGs), DNA single-strand breaks (SSBs), DNA-protein crosslinks (DPCs), chromosomal aberrations (CAs), in situ MT expression, and cell proliferation in rat liver preneoplasia. Hepatocarcinogenesis was induced in male Sprague-Dawley rats with a single, necrogenic, intraperitoneal (i.p.) injection of diethylnitrosamine (DEN) (200 mg/Kg body weight) at week 4 of the experimental protocol followed by promotion with phenobarbital (PB) (0.05% in basal diet), on and from week 8 and continued till 32 weeks in a long-term regimen. There was a significant and steady elevation of modified DNA bases 8-OHdGs (P < 0.0001; 90.69%) along with substantial increments of the extent of SSBs (P < 0.001) and CAs (P < 0.001) following DEN exposure. Supplementation of vanadium at a dose of 0.5 ppm abated the formations of 8-OHdGs (80.63%; P < 0.0001), SS-DNAs (P < 0.001) and SSBs/DNA unit (P < 0.01; 56.39%), DPCs (59.26%; P < 0.0001) and CAs (71.52%; P < 0.001) in preneoplastic rat liver studied at various time points. Low dose of vanadium treatment further reduced liver-MT immunoreactivity (P < 0.05) and BrdU-labeling index (P < 0.02) and a significant positive correlation (r = 0.92; r2 = 0.85; P = 0.0001) was noted between them. Continuous vanadium administration also decreased nodular incidence (66.67%) and nodule multiplicity (62.12%; P < 0.001) along with substantial improvement in the altered hepatocellular phenotype when compared to DEN + PB treatment alone. The study indicates that vanadium-mediated suppression of cell proliferation and resulting premalignant expression might be due to the observed reductions in hepatic 8-OHdGs, SSBs, DPCs, CAs, and MT immunoreactivity. Vanadium is chemopreventive for DEN-induced hepatocellular preneoplasia in rats.
致癌物诱导的早期DNA损伤和金属硫蛋白（MT）的过度表达与细胞增殖有关，进而与细胞癌前表型的后续表达有关。因此，我们采用多生物标志物方法研究了钒的化学预防潜力，即8-羟基-2'-脱氧鸟苷（8-OHdGs）、DNA单链断裂（SSBs）、DNA-蛋白质交联（DPCs）、染色体畸变（CAs）、原位MT表达以及大鼠肝癌前病变中的细胞增殖。在实验方案的第4周，对雄性Sprague-Dawley大鼠进行单次腹腔内（i.p.）注射致坏死性二乙基亚硝胺（DEN）（200 mg/Kg体重）诱导肝癌发生，随后从第8周开始用苯巴比妥（PB）（基础饮食中0.05%）进行促癌，持续至32周，采用长期方案。DEN暴露后，修饰的DNA碱基8-OHdGs显著且稳定升高（P < 0.0001；90.69%），同时SSBs（P < 0.001）和CAs（P < 0.001）的程度大幅增加。以0.5 ppm的剂量补充钒可减少不同时间点研究的癌前大鼠肝脏中8-OHdGs（80.63%；P < 0.0001）、单链DNA（SS-DNAs）（P < 0.001）和SSBs/DNA单位（P < 0.01；56.39%）、DPCs（59.26%；P < 0.0001）和CAs（71.52%；P < 0.001）的形成。低剂量钒处理进一步降低了肝脏MT免疫反应性（P < 0.05）和BrdU标记指数（P < 0.02），并且二者之间存在显著正相关（r = 0.92；r2 = 0.85；P = 0.0001）。与单独的DEN + PB处理相比，持续给予钒还降低了结节发生率（66.67%）和结节多发性（62.12%；P < 0.001），同时显著改善了改变的肝细胞表型。该研究表明，钒介导的细胞增殖抑制及由此产生的癌前表达可能是由于观察到的肝脏8-OHdGs、SSBs、DPCs、CAs和MT免疫反应性的降低。钒对DEN诱导的大鼠肝细胞癌前病变具有化学预防作用。
