Reversal of Ethanol and Indomethacin–Induced Suppression of Hepatic Dna Synthesis by 16,16–Dimethyl Prostaglandin E2

Abstract

Investigations were undertaken to determine effectiveness of 16,16–dimethyl prostaglandin E₂ (dmPGE₂) in overcoming the suppressive effects of ethanol and/or indomethacin on hepatic DNA synthesis. Adult litter mate Sprague–Dawley rats were subjected to sham operation or partial hepatectomy. Immediately after partial hepatectomy, and at 8–hr intervals for 24 hr, the rats were given: (a) ethanol with and without dmPGE₂ or (b) indomethacin with and without ethanol and/or dmPGE₂. DmPGE₂ produced a significant increase in DNA synthesis in sham–operated (p < 0.001) and untreated partially hepatectomized animals (p < 0.025). Ethanol and indomethacin caused a 6– and 18–fold reduction, respectively, in hepatic DNA synthesis following partial hepatectomy. DmPGE₂ overcame the inhibitory effect of ethanol (p < 0.005) and indomethacin (p < 0.0005) in partially hepatectomized animals. Mitoses were decreased concomitantly with ethanol and/or indomethacin–induced reduction in DNA synthesis and increased with administration of dmPGE₂. It is concluded that dmPGE₂ increases hepatic DNA synthesis and regeneration in normal rat liver and overcomes their inhibition when ethanol and/or indomethacin is given after partial hepatectomy. Timing of dmPGEz administration is crucial. When given 30 min before ethanol, it completely inhibits suppression of regenerative activity; omission of this “priming” dmPGE₂ dose results in only 44% of DNA synthesis obtained in control animals.