title: Different mechanisms for histone acetylation by ethanol and its metabolite acetate in rat primary hepatocytes.
abstract: Ethanol and its major metabolite acetate both induced histone H3 acetylation in primary culture of rat hepatocytes. The acetylation by ethanol was dependent on the reactive oxygen species and mitogen-activated protein kinase pathway, whereas that by acetate was independent of both pathways. Ethanol increased CYP2E1 protein expression but acetate had negligible effect. The level of phospho-H2AX, an indicator of DNA breaks, was elevated by ethanol but not by acetate. Ethanol and acetate differentially activated mRNA expression for different genes, e.g., IL-6, PPARγ, c-Fos, Egr-1, and PNPLA3 in hepatocytes. The most striking increase (3-fold) was in PNPLA3 mRNA by ethanol with little change by acetate. It was further shown that acetate inhibited histone deacetylase activity. Taken together, these data establish for the first time that ethanol and acetate exhibit differences in their effects on hepatocytes in gene expression, P-H2AX levels, and the mechanism of histone H3 acetylation. The implications of these differences in the actions of ethanol in liver are discussed.
authors.affiliation: Department of Medical Pharmacology and Physiology (S.D.S., R.R., P.F., R.W.L., J.A.I.) and Department of Internal Medicine (J.A.I.), University of Missouri School of Medicine, Columbia, Missouri shuklasd@missouri.edu.
authors.forename: Shivendra D
authors.initials: SD
authors.lastname: Shukla
authors.affiliation: Department of Medical Pharmacology and Physiology (S.D.S., R.R., P.F., R.W.L., J.A.I.) and Department of Internal Medicine (J.A.I.), University of Missouri School of Medicine, Columbia, Missouri.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Restrepo
authors.affiliation: Department of Medical Pharmacology and Physiology (S.D.S., R.R., P.F., R.W.L., J.A.I.) and Department of Internal Medicine (J.A.I.), University of Missouri School of Medicine, Columbia, Missouri.
authors.forename: Philip
authors.initials: P
authors.lastname: Fish
authors.affiliation: Department of Medical Pharmacology and Physiology (S.D.S., R.R., P.F., R.W.L., J.A.I.) and Department of Internal Medicine (J.A.I.), University of Missouri School of Medicine, Columbia, Missouri.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Lim
authors.affiliation: Department of Medical Pharmacology and Physiology (S.D.S., R.R., P.F., R.W.L., J.A.I.) and Department of Internal Medicine (J.A.I.), University of Missouri School of Medicine, Columbia, Missouri.
authors.forename: Jamal A
authors.initials: JA
authors.lastname: Ibdah
mesh_terms: D000085:Acetates / Q000378:metabolism / Q000494:pharmacology*; D000107:Acetylation; D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000085:Acetates; D006657:Histones; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D020928:Mitogen-Activated Protein Kinases; D006655:Histone Deacetylases