title: Identification of a novel set of biomarkers for evaluating phospholipidosis-inducing potential of compounds using rat liver microarray data measured 24-h after single dose administration.
abstract: Phospholipid accumulation manifests as an adverse effect of cationic amphiphilic drugs in particular. Detection, however, by histopathology examination is time-consuming and may require repeated administration of compounds for several weeks. To eliminate compounds with potential for inducing phospholipidosis from the discovery pipeline, we have identified and validated a set of biomarkers for predicting the phospholipidosis-inducing potential utilizing a comprehensive rat transcriptome microarray database created by the Japanese Toxicogenomics and Toxicogenomics Informatics Projects (TGP/TGP2) together with in-house data. The set of biomarkers comprising 25 Affymetrix GeneChip probe sets was identified using genetic algorithm optimization on 24-h time-point microarray data from rats treated with single doses of hepatotoxic compounds including amiodarone, clomipramine, haloperidol, hydroxyzine, imipramine, and perhexiline. The set of novel biomarkers represents an early time-point gene-expression pattern characteristic for a condition eventually leading to phospholipidosis. This implies significant advantages in terms of time and resources over currently published biomarkers derived using repeated-dosing late time-point data. The biomarker set was validated by 11 independent compounds. Accuracy, sensitivity, and specificity values were 82%, 67%, and 100%, respectively and the area under the receiver operating characteristic curve was 0.97. These results show that the biomarker set possesses a high classification accuracy for novel compounds. Pathway analysis was carried out for the biomarkers and the detection of pathways related to lipid-metabolism was statistically significant. These pathways most probably reflect lipid metabolism changes associated with phospholipidosis supporting the validity of our novel biomarkers.
authors.affiliation: Genomic Science Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Japan.
authors.forename: Henrik T
authors.initials: HT
authors.lastname: Yudate
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kai
authors.forename: Mikio
authors.initials: M
authors.lastname: Aoki
authors.forename: Yohsuke
authors.initials: Y
authors.lastname: Minowa
authors.forename: Toru
authors.initials: T
authors.lastname: Yamada
authors.forename: Toru
authors.initials: T
authors.lastname: Kimura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ono
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ohno
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Urushidani
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D008064:Lipidoses / Q000139:chemically induced*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010743:Phospholipids / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D046888:Tissue Array Analysis
chemical_list: D015415:Biomarkers; D010743:Phospholipids