title: Utilization of causal reasoning of hepatic gene expression in rats to identify molecular pathways of idiosyncratic drug-induced liver injury.
abstract: Drug-induced liver injury (DILI) represents a leading cause of acute liver failure. Although DILI can be discovered in preclinical animal toxicology studies and/or early clinical trials, some human DILI reactions, termed idiosyncratic DILI (IDILI), are less predictable, occur in a small number of individuals, and do not follow a clear dose-response relationship. The emergence of IDILI poses a critical health challenge for patients and a financial challenge for the pharmaceutical industry. Understanding the cellular and molecular mechanisms underlying IDILI is key to the development of models that can assess potential IDILI risk. This study used Reverse Causal Reasoning (RCR), a method to assess activation of molecular signaling pathways, on gene expression data from rats treated with IDILI or pharmacologic/chemical comparators (NON-DILI) at the maximum tolerated dose to identify mechanistic pathways underlying IDILI. Detailed molecular networks involved in mitochondrial injury, inflammation, and endoplasmic reticulum (ER) stress were found in response to IDILI drugs but not negative controls (NON-DILI). In vitro assays assessing mitochondrial or ER function confirmed the effect of IDILI compounds on these systems. Together our work suggests that using gene expression data can aid in understanding mechanisms underlying IDILI and can guide in vitro screening for IDILI. Specifically, RCR should be considered for compounds that do not show evidence of DILI in preclinical animal studies positive for mitochondrial dysfunction and ER stress assays, especially when the therapeutic index toward projected human maximum drug plasma concentration is low.
authors.affiliation: * Selventa Inc., Cambridge, Massachusetts 02140;
authors.forename: Daphna
authors.initials: D
authors.lastname: Laifenfeld
authors.forename: Luping
authors.initials: L
authors.lastname: Qiu
authors.forename: Rachel
authors.initials: R
authors.lastname: Swiss
authors.forename: Jennifer
authors.initials: J
authors.lastname: Park
authors.forename: Michael
authors.initials: M
authors.lastname: Macoritto
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Will
authors.forename: Husam S
authors.initials: HS
authors.lastname: Younis
authors.forename: Michael
authors.initials: M
authors.lastname: Lawton
mesh_terms: D000818:Animals; D001185:Artificial Intelligence; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D012307:Risk Factors; D049490:Systems Biology; D013997:Time Factors; D043922:Toxicogenetics / Q000379:methods*
chemical_list: D018836:Inflammation Mediators
keywords: biological modeling; liver; risk assessment; safety evaluation; systems biology; systems toxicology.; toxicogenomics