title: Acrolein enhances epigenetic modifications, FasL expression and hepatocyte toxicity induced by anti-HIV drug Zidovudine.
abstract: Zidovudine (AZT) remains the mainstay of antiretroviral therapy against HIV in resource-poor countries; however, its use is frequently associated with hepatotoxicity. Not all HIV patients on AZT develop hepatotoxicity, and the determining factors are unclear. Alcohol consumption and cigarette smoking are known risk factors for HIV hepatotoxicity, and both are significant sources of acrolein, a highly reactive and toxic aldehyde. This study examines the potential hepatotoxic interactions between acrolein and AZT. Our data demonstrate that acrolein markedly enhanced AZT-induced transcriptionally permissive histone modifications (H3K9Ac and H3K9Me3) allowing the recruitment of transcription factor NF-kB and RNA polymerase II at the FasL gene promoter, resulting in FasL upregulation and apoptosis in hepatocytes. Notably, the acrolein scavenger, hydralazine prevented these promoter-associated epigenetic changes and inhibited FasL upregulation and apoptosis induced by the combination of AZT and acrolein, as well as AZT alone. Our data strongly suggest that acrolein enhancement of promoter histone modifications and FasL upregulation are major pathogenic mechanisms driving AZT-induced hepatotoxicity. Moreover, these data also indicate the therapeutic potential of hydralazine in mitigating AZT hepatotoxicity.
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Smita S
authors.initials: SS
authors.lastname: Ghare
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Hridgandh
authors.initials: H
authors.lastname: Donde
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Wei-Yang
authors.initials: WY
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Barker
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Gobejishvilli
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Shirish S
authors.initials: SS
authors.lastname: Barve
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; University of Louisville, Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA. Electronic address: s0josh01@louisville.edu.
authors.forename: Swati
authors.initials: S
authors.lastname: Joshi-Barve
mesh_terms: D000171:Acrolein / Q000633:toxicity*; D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation; D044127:Epigenesis, Genetic / Q000187:drug effects*; D053222:Fas Ligand Protein / Q000235:genetics*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006657:Histones / Q000235:genetics; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D012319:RNA Polymerase II / Q000235:genetics; D051381:Rats; D015215:Zidovudine / Q000633:toxicity*
chemical_list: D019380:Anti-HIV Agents; D053222:Fas Ligand Protein; D006657:Histones; D006830:Hydralazine; D015215:Zidovudine; D000171:Acrolein; D012319:RNA Polymerase II
keywords: Acrolein; Epigenetic promoter modifications; FasL; Hepatocytes; Hydralazine; Zidovudine (AZT)