title: Alcohol potentiates hepatitis C virus replicon expression.
abstract: Alcohol consumption accelerates liver damage and diminishes the anti-hepatitis C virus (HCV) effect of interferon alfa (IFN-alpha) in patients with HCV infection. It is unknown, however, whether alcohol enhances HCV replication and promotes HCV disease progression. The availability of the HCV replicon containing hepatic cells has provided a unique opportunity to investigate the interaction between alcohol and HCV replicon expression. We determined whether alcohol enhances HCV RNA expression in the replicon containing hepatic cells. Alcohol, in a concentration-dependent fashion, significantly increased HCV replicon expression. Alcohol also compromised the anti-HCV effect of IFN-alpha. Investigation of the mechanism(s) responsible for the alcohol action on HCV replicon indicated that alcohol activated nuclear factor kappaB (NF-kappaB) promoter. Caffeic acid phenethyl ester (CAPE), a specific inhibitor of the activation of NF-kappaB, abolished alcohol-induced HCV RNA expression. In addition, naltrexone, an opiate receptor antagonist, abrogated the enhancing effect of alcohol on HCV replicon expression. In conclusion, alcohol, probably through the activation of NF-kappaB and the endogenous opioid system, enhances HCV replicon expression and compromises the anti-HCV effect of IFN-alpha. Thus, alcohol may play an important role in vivo as a cofactor in HCV disease progression and compromise IFN-alpha-based therapy against HCV infection.
authors.affiliation: Division of Allergy and Immunology, Joseph Stokes Jr. Research Institute at The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Lai
authors.forename: Steven D
authors.initials: SD
authors.lastname: Douglas
authors.forename: David S
authors.initials: DS
authors.lastname: Metzger
authors.forename: Charles P
authors.initials: CP
authors.lastname: O'Brien
authors.forename: Wen-Zhe
authors.initials: WZ
authors.lastname: Ho
mesh_terms: D000931:Antidotes / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003484:Cyanamide / Q000494:pharmacology; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D000077604:Fomepizole; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000254:growth & development*; D019698:Hepatitis C, Chronic / Q000821:virology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012367:RNA, Viral / Q000378:metabolism; D012093:Replicon / Q000187:drug effects* / Q000502:physiology
chemical_list: D000931:Antidotes; D000998:Antiviral Agents; D002492:Central Nervous System Depressants; D016328:NF-kappa B; D009292:Narcotic Antagonists; D011720:Pyrazoles; D012367:RNA, Viral; D000431:Ethanol; D003484:Cyanamide; D009271:Naltrexone; D007371:Interferon-gamma; D000077604:Fomepizole