Inhibition of astroglial cell proliferation by alcohols: interference with the protein kinase C-phospholipase D signaling pathway.
Ethanol inhibits astroglial cell proliferation, an effect that may contribute to the development of alcoholic embryopathy in humans. In the present study, we investigated inhibitory effects of ethanol and butanol isomers (1-, 2- and t-butanol) on astroglial cell proliferation induced by the strongly mitogenic phorbol ester, 4beta-phorbol-12alpha,13beta-dibutyrate (PDB). 4beta-Phorbol-12alpha,13beta-dibutyrate (PDB) induced a 10-fold increase of [3H] thymidine incorporation in cortical astrocytes prepared from newborn rats (EC50: 70 nM) which was blocked by Ro 31-8220, a cell-permeable protein kinase C (PKC) inhibitor. Ethanol blocked PDB-induced astroglial proliferation in a concentration-dependent manner; significant effects were already seen at 0.1% (v/v). Concomitantly, ethanol caused the formation of phosphatidylethanol (PEth) by phospholipase D (PLD) and reduced PLD-mediated formation of phosphatidic acid (PA). The butanols also inhibited the mitogenic action of phorbol ester; the inhibitory potency of the butanols was 1-butanol > 2-butanol > t-butanol. The same range of potencies was observed for the inhibitory activity of the butanols towards protein kinase C activity measured in vitro. At 0.3% concentration, 1-butanol potently suppressed the PDB-induced formation of phosphatidic acid while 2- and t-butanol were less active. Taken together, our results suggest that ethanol and 1-butanol exert a specific inhibitory effect on PKC-dependent astroglial cell proliferation by synergistically inhibiting PKC activity and the PLD signaling pathway.
Kötter
K
K
Department of Pharmacology, University of Mainz, Germany.
Jin
S
S
Klein
J
J
D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D001921:Brain / Q000166:cytology; D000440:Butanols / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004075:Diglycerides / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000096:biosynthesis; D010739:Phospholipase D / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D000440:Butanols; D002273:Carcinogens; D002492:Central Nervous System Depressants; D004075:Diglycerides; D004791:Enzyme Inhibitors; D007211:Indoles; D010703:Phorbol Esters; D010712:Phosphatidic Acids; D015240:Phorbol 12,13-Dibutyrate; D000431:Ethanol; D011493:Protein Kinase C; D010739:Phospholipase D; C064758:Ro 31-8220