Enhanced GABA(B) receptor in neoplastic rat liver: induction of DNA synthesis by baclofen in hepatocyte cultures.
In the present study, the involvement of GABA(B) binding parameters were analyzed in partial hepatectomized (PH), lead nitrate (LN) induced hyperplastic and N-nitrosodiethylamine (NDEA) treated neoplastic rat livers at the peak DNA synthesis. The receptor up-regulated significantly in NDEA treated group compared with respective control. The affinity of the receptor decreased in PH while it increased in LN treated rats. In the other groups, the binding parameters remained unaltered. The displacement analysis using GABA(B) receptor agonist, [3H]baclofen, against baclofen showed a shift in affinity of the receptor towards high-affinity in PH rats and towards low-affinity in LN treated rats. Baclofen dose-dependently induced EGF mediated DNA synthesis in primary hepatocyte cultures. Also, it significantly reduced the TGFbeta1 suppression of EGF induced DNA synthesis. The effect of baclofen on hepatocyte DNA synthesis was abolished by the addition of G(i)-protein inhibitor, pertussis toxin, suggesting the involvement of GABA(B) receptor mechanisms in hepatocyte DNA synthesis. Baclofen alone could not elicit any significant change in DNA synthesis. Thus, our results show that GABA(B) receptor enhancement induce hepatic neoplasia. Also, baclofen is seen to act as a potent co-mitogen, triggering DNA synthesis in primary cultures of rat hepatocytes, mediated through the G(i) protein coupled GABA(B) receptors.
Biju
Mangatt P
MP
Department of Biotechnology, Molecular Neurobiology and Cell Biology Unit, Centre for Neuroscience, Cochin University of Science and Technology, Kochi 682 022, India.
Pyroja
Sulaiman
S
Rajeshkumar
Neelimmathara V
NV
Paulose
Cheramadathikudyil S
CS
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002455:Cell Division; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004052:Diethylnitrosamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism*; D007700:Kinetics; D007854:Lead / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D008934:Mitogens / Q000494:pharmacology; D009566:Nitrates / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000737:chemistry* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000477:Alkylating Agents; D018755:GABA Agonists; D008934:Mitogens; D009566:Nitrates; D018080:Receptors, GABA-B; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D007854:Lead; D004052:Diethylnitrosamine; C017461:lead nitrate; D004247:DNA; D001418:Baclofen