Development of an adverse outcome pathway from drug-mediated bile salt export pump inhibition to cholestatic liver injury.
Adverse outcome pathways (AOPs) have been recently introduced in human risk assessment as pragmatic tools with multiple applications. As such, AOPs intend to provide a clear-cut mechanistic representation of pertinent toxicological effects. AOPs are typically composed of a molecular initiating event, a series of intermediate steps and key events, and an adverse outcome. In this study, an AOP framework is proposed for cholestasis triggered by drug-mediated inhibition of the bile salt export pump transporter protein. For this purpose, an in-depth survey of relevant scientific literature was carried out in order to identify intermediate steps and key events. The latter include bile accumulation, the induction of oxidative stress and inflammation, and the activation of specific nuclear receptors. Collectively, these mechanisms drive both a deteriorative cellular response, which underlies directly caused cholestatic injury, and an adaptive cellular response, which is aimed at counteracting cholestatic insults. AOP development was performed according to Organisation for Economic Co-operation and Development (OECD) guidance, including critical consideration of the Bradford Hill criteria for weight of evidence assessment and the OECD key questions for evaluating AOP confidence. The postulated AOP is expected to serve as the basis for the development of new in vitro tests and the characterization of novel biomarkers of drug-induced cholestasis.
* Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel (VUB), B-1090 Brussels, Belgium;
Mathieu
M
Vinken
Brigitte
B
Landesmann
Marina
M
Goumenou
Stefanie
S
Vinken
Imran
I
Shah
Hartmut
H
Jaeschke
Catherine
C
Willett
Maurice
M
Whelan
Vera
V
Rogiers
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000826:Animal Testing Alternatives; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D014116:Toxicology / Q000379:methods*
C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters
adverse outcome pathway.; cholestasis; drug-induced liver injury