Molecular basis of vanadium-mediated inhibition of hepatocellular preneoplasia during experimental hepatocarcinogenesis in rats.
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.
Chakraborty
Tridib
T
Division of Biochemistry, Department of Pharmaceutical Technology, Jadavpur University, PO Box 17028, Calcutta-700032, West-Bengal, India.
Swamy
A H M Viswanatha
AH
Chatterjee
Amrita
A
Rana
Basabi
B
Shyamsundar
A
A
Chatterjee
Malay
M
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D018890:Chemoprevention / Q000379:methods; D004249:DNA Damage; D004052:Diethylnitrosamine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D010634:Phenobarbital / Q000633:toxicity; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014639:Vanadium / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D014639:Vanadium; D004052:Diethylnitrosamine; D010634:Phenobarbital