Stimulation of DNA synthesis and proliferation by prostaglandins in primary cultures of adult rat hepatocytes.
We studied the effects of several prostaglandins on DNA synthesis and proliferation in serum-free primary cultures of adult rat hepatocytes. Maintained in short-term cultures (i.e., 3.5 h), the hepatocyte parenchymal cells synthesized DNA and proliferated in the presence of various prostaglandins in a dose-dependent manner. The half-maximal effective concentrations (ED(50)) of prostaglandin F(2alpha), prostaglandin E(1), prostaglandin E(2) and prostaglandin I(2) for proliferation were estimated to be 1.7 x 10(-9), 2.3 x 10(-8), 2.7 x 10(-8) and 3.3 x 10(-9) M, respectively. Prostaglandin E(2) and prostaglandin I(2) produced greater maximal responses than did either prostaglandin E(1) or prostaglandin F(2alpha). The cells responded only weakly to prostaglandin D(2). The stimulatory effects of 10(-6) M prostaglandin E(1) and 10(-6) M prostaglandin E(2) on hepatocyte DNA synthesis and proliferation were inhibited by a specific antagonist of the EP(1) receptor, 8-chlorodibenz[b, f][1, 4]oxazepine-10(11H)carboxylic acid, 2-[3-[(2-furanylmethyl)-thio]-1-oxopropyl]hydrazide (SC-51322; 10(-6) M). Specific inhibitors of signal transducing elements (e.g., 1-[6-[17beta-3-methoxyestra-1, 3, 5(10)-trien-17-yl]amino] hexyl]-1H-pyrrol-2,5-dione (U-73122); 10(-6) M), 10(-6) M verapamil, 5 x 10(-6) M genistein) almost completely blocked the growth-promoting effects of the prostaglandins. These results suggest that prostaglandins stimulate hepatocyte DNA synthesis and proliferation by their own receptors and exert their effects through both phospholipase C/Ca(2+) and receptor tyrosine kinase pathways.
Kimura
M
M
Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, 350-0295, Sakado City, Japan.
Osumi
S
S
Ogihara
M
M
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011453:Prostaglandins / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D004247:DNA