title: Drug-induced Liver Fibrosis: Testing Nevirapine in a Viral-like Liver Setting Using Histopathology, MALDI IMS, and Gene Expression.
abstract: Nevirapine (NVP) is associated with hepatotoxicity in 1-5% of patients. In rodent studies, NVP has been shown to cause hepatic enzyme induction, centrilobular hypertrophy, and skin rash in various rat strains but not liver toxicity. In an effort to understand whether NVP is metabolized differently in a transiently inflamed liver and whether a heightened immune response alters NVP-induced hepatic responses, female brown Norway rats were dosed with either vehicle or NVP alone (75 mg/kg/day for 15 days) or galactosamine alone (single intraperitoneal [ip] injection on day 7 to mimic viral hepatitis) or a combination of NVP (75/100/150 mg/kg/day for 15 days) and galactosamine (single 750 mg/kg ip on day 7). Livers were collected at necropsy for histopathology, matrix-assisted laser desorption/ionization imaging mass spectrometry and gene expression. Eight days after galactosamine, hepatic fibrosis was noted in rats dosed with the combination of NVP and galactosamine. No fibrosis occurred with NVP alone or galactosamine alone. Gene expression data suggested a viral-like response initiated by galactosamine via RNA sensors leading to apoptosis, toll-like receptor, and dendritic cell responses. These were exacerbated by NVP-induced growth factor, retinol, apoptosis, and periostin effects. This finding supports clinical reports warning against exacerbation of fibrosis by NVP in patients with hepatitis C.
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: H Roger
authors.initials: HR
authors.lastname: Brown
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Castellino
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: M Reid
authors.initials: MR
authors.lastname: Groseclose
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA chandi.s.elangbam@gsk.com.
authors.forename: Chandikumar S
authors.initials: CS
authors.lastname: Elangbam
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Mellon-Kusibab
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Yoon
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Gates
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Krull
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Neal F
authors.initials: NF
authors.lastname: Cariello
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Leigh
authors.initials: L
authors.lastname: Arrington-Brown
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Tillman
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Serita
authors.initials: S
authors.lastname: Fowler
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Vishal
authors.initials: V
authors.lastname: Shah
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: David
authors.initials: D
authors.lastname: Bailey
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Miller
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity; D005260:Female; D005688:Galactosamine / Q000633:toxicity; D020869:Gene Expression Profiling; D006651:Histocytochemistry; D008099:Liver / Q000473:pathology* / Q000821:virology; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000473:pathology*; D019829:Nevirapine / Q000633:toxicity*; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000998:Antiviral Agents; D005688:Galactosamine; D019829:Nevirapine
keywords: M2 macrophages; galactosamine; hepatic fibrosis; lipocalin 2; nevirapine; periostin; sgpl1