title: Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition.
abstract: The effects of the dietary antioxidant N-acetylcysteine (NAC) on alcoholic liver damage were examined in a total enteral nutrition (TEN) model of ethanol toxicity in which liver pathology occurs in the absence of endotoxemia. Ethanol treatment resulted in steatosis, inflammatory infiltrates, occasional foci of necrosis, and elevated ALT in the absence of increased expression of the endotoxin receptor CD 14, a marker of Kupffer cell activation by LPS. In addition, ethanol treatment induced CYP 2 E1 and increased TNFalpha and TGFbeta mRNA expression accompanied by suppressed hepatic IL-4 mRNA expression. Ethanol treatment also resulted in the hepatic accumulation of malondialdehyde (MDA) and hydroxynonenal (HNE) protein adducts, decreased antioxidant capacity, and increased antibody titers toward serum hydroxyethyl radical (HER), MDA, and HNE adducts. NAC treatment increased cytosolic antioxidant capacity, abolished ethanol-induced lipid peroxidation, and inhibited the formation of antibodies toward HNE and HER adducts without interfering with CYP 2 E1 induction. NAC also decreased ethanol-induced ALT release and inflammation and prevented significant loss of hepatic GSH content. However, the improvement in necrosis score and reduction of TNFalpha mRNA elevation did not reach statistical significance. Although a direct correlation was observed among hepatic MDA and HNE adduct content and TNFalpha mRNA expression, inflammation, and necrosis scores, no correlation was observed between oxidative stress markers or TNFalpha and steatosis score. These data suggest that ethanol-induced oxidative stress can contribute to inflammation and liver injury even in the absence of Kupffer cell activation by endotoxemia.
authors.affiliation: Arkansas Children's Nutrition Center; University of Arkansas for Medical Sciences, Little Rock, AR, USA. RonisMartinJ@uams.edu
authors.forename: Martin J J
authors.initials: MJ
authors.lastname: Ronis
authors.forename: Angelica
authors.initials: A
authors.lastname: Butura
authors.forename: Brante P
authors.initials: BP
authors.lastname: Sampey
authors.forename: Kartik
authors.initials: K
authors.lastname: Shankar
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Prior
authors.forename: Sohelia
authors.initials: S
authors.lastname: Korourian
authors.forename: Emanuele
authors.initials: E
authors.lastname: Albano
authors.forename: Magnus
authors.initials: M
authors.lastname: Ingelman-Sundberg
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Petersen
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Badger
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002417:Cattle; D002492:Central Nervous System Depressants / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004750:Enteral Nutrition; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology* / Q000652:urine; D005978:Glutathione / Q000378:metabolism; D007107:Immune System; D007150:Immunohistochemistry; D007249:Inflammation; D007728:Kupffer Cells / Q000378:metabolism; D015227:Lipid Peroxidation; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008233:Lymphotoxin-alpha / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009336:Necrosis; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D002492:Central Nervous System Depressants; D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008233:Lymphotoxin-alpha; D016877:Oxidants; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C065424:1-hydroxyethyl radical; D000431:Ethanol; D008315:Malondialdehyde; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione; C027576:4-hydroxy-2-nonenal; D000111:Acetylcysteine