Effects of acute and chronic ethanol exposure on the hepatic gamma-aminobutyric acid transport system in rats.
Ethanol-induced increases in gamma-aminobutyric (GABA)ergic activity contribute to the impairment in hepatic regeneration associated with alcohol-induced liver disease. To determine the mechanism(s) whereby ethanol increases GABAergic activity in the liver, we documented the effects of acute (5 g/kg x 1) and chronic (36% of total calories over 6 weeks) ethanol exposure as well as exogenous GABA (500 microg/g body weight) administration on GABA transport protein (GABA-TP) mRNA expression in the livers of adult male Sprague-Dawley rats at various times (0-72 h) post 70% partial hepatectomy (PHx). We also documented the in vitro effects of ethanol (30-90 microM) on [3H]-GABA uptake in isolated rat hepatocytes. The results of the study revealed that compared to saline-exposed controls, acute but not chronic ethanol exposure resulted in significant decreases in GABA-TP mRNA expression at 12, 24, and 48 h post PHx (saline exposed, 1.04 +/- 0.06, 1.19 +/- 0.21, and 1.15 +/- 0.05. vs. acute ethanol exposed, 0.80 +/- 0.16, 0.88 +/- 0.09, and 0.86 +/- 0.16 optical density units, p < 0.01, 0.05, and 0.05, respectively). An inhibitory effect was also observed following exogenous GABA administration (GABA-TP mRNA expression at 3 h was approximately 40% that of baseline, p < 0.05). [3H]-GABA uptake in isolated rat hepatocytes in vitro was unaffected by the presence of ethanol. In conclusion, the results of this study indicate that acute but not chronic ethanol exposure and exogenously administrated GABA inhibit hepatic GABA-TP mRNA expression following partial hepatectomy in the rat. These findings suggest that the increased GABAergic activity that occurs in the liver following acute ethanol exposure results from alterations in the hepatic GABA transport system at a transcriptional level.
Gong
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Y
Department of Medicine, University of Manitoba, Winnipeg, Canada.
Cui
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Minuk
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GY
D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D050485:GABA Plasma Membrane Transport Proteins; D006498:Hepatectomy; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects* / Q000378:metabolism; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D005680:gamma-Aminobutyric Acid / Q000187:drug effects* / Q000378:metabolism
D002352:Carrier Proteins; D002492:Central Nervous System Depressants; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D012333:RNA, Messenger; D000431:Ethanol; D005680:gamma-Aminobutyric Acid