Abstract
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; r^2^ = 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. J. Cell. Biochem. 101: 244–258, 2007. © 2007 Wiley‐Liss, Inc.