title: Prediction of drug-induced liver injury using keratinocytes.
abstract: Drug-induced liver injury (DILI) is one of the most common adverse drug reactions. DILI is often accompanied by skin reactions, including rash and pruritus. However, it is still unknown whether DILI-associated genes such as S100 calcium-binding protein A and interleukin (IL)-1β are involved in drug-induced skin toxicity. In the present study, most of the tested hepatotoxic drugs such as pioglitazone and diclofenac induced DILI-associated genes in human and mouse keratinocytes. Keratinocytes of mice at higher risk for DILI exhibited an increased IL-1β basal expression. They also showed a higher inducibility of IL-1β when treated by pioglitazone. Mice at higher risk for DILI showed even higher sums of DILI-associated gene basal expression levels and induction rates in keratinocytes. Our data suggest that DILI-associated genes might be involved in the onset and progression of drug-induced skin toxicity. Furthermore, we might be able to identify individuals at higher risk of developing DILI less invasively by examining gene expression patterns in keratinocytes. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Hirashima
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Laboratory of Environmental Toxicology, Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Tukey
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Fujiwara
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002135:Calcium-Binding Proteins; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000473:pathology*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology* / Q000235:genetics*; D005260:Female; D015386:Hazardous Substances / Q000633:toxicity*; D006801:Humans; D053583:Interleukin-1beta; D015603:Keratinocytes / Q000187:drug effects*; D008099:Liver / Q000503:physiopathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D004364:Pharmaceutical Preparations
chemical_list: D002135:Calcium-Binding Proteins; D015386:Hazardous Substances; D053583:Interleukin-1beta; D004364:Pharmaceutical Preparations
keywords: IL-1β; drug-induced liver injury; hepatotoxicity; keratinocyte; prediction