title: Both cholestatic and steatotic drugs trigger extensive alterations in the mRNA level of biliary transporters in rat hepatocytes: Application to develop new predictive biomarkers for early drug development.
abstract: Disruption of the vectorial bile acid transport in the liver is a key feature of cholestatic drugs, although many causal and mechanistic aspects are still unknown. The aim of the present study was to explore if cholestatic drugs can repress or induce the expression of hepatic transporters. To this end, sandwich-cultured rat hepatocytes were treated with cholestatic and non-cholestatic (steatotic, non-hepatotoxic, etc.) drugs and the mRNA expression of 10 uptake and efflux biliary transporters was measured. Results evidenced that all cholestatic drugs cause extensive alterations in the mRNA expression of most biliary transporters. Surprisingly, nearly all steatotic drugs also affected the expression of these genes. The most frequent alterations triggered by both types of drugs were the repression of OATP1A1, NTCP and BSEP, and the induction of MRP2/3/4, MDR2 and ABCG5/8. The majority of these alterations were also observed in vivo, in the livers of treated rats. The common signature of cholestatic and steatotic drugs was the repression of OATP1A1. Indeed, ROC curve analysis indicated that OATP1A1 mRNA is a very sensitive marker to identify drugs with cholestatic or steatotic potential, with a maximal sensitivity and specificity of 0.917 and 0.941, respectively. We conclude that alteration of expression of hepatobiliary transporters is a hallmark of both cholestatic and steatotic drugs, lending support to a connection between these two mechanisms of hepatotoxicity. Moreover, OATP1A1 mRNA is proposed as a very simple and useful screening biomarker for the prediction of new cholestatic or steatotic drugs in early drug development.
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, 46026-Valencia, Spain; CIBERehd, ISCIII, Madrid, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010-Valencia, Spain.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Donato
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, 46026-Valencia, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: López-Riera
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, 46026-Valencia, Spain; CIBERehd, ISCIII, Madrid, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010-Valencia, Spain.
authors.forename: José V
authors.initials: JV
authors.lastname: Castell
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, 46026-Valencia, Spain; CIBERehd, ISCIII, Madrid, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Gómez-Lechón
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, 46026-Valencia, Spain; CIBERehd, ISCIII, Madrid, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010-Valencia, Spain. Electronic address: ramiro.jover@uv.es.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Jover
mesh_terms: D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D015415:Biomarkers / Q000032:analysis*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism*; D002478:Cells, Cultured; D002779:Cholestasis / Q000139:chemically induced*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D005234:Fatty Liver / Q000139:chemically induced*; D022781:Hepatocytes / Q000187:drug effects*; D008297:Male; D029362:Organic Anion Transporters, Sodium-Independent / Q000032:analysis / Q000378:metabolism; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013754:Tetracyclines / Q000633:toxicity
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; C000609070:Oatp1a1 protein, rat; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; D013754:Tetracyclines
keywords: Biliary transporter; Cholestasis; Drug-induced liver injury; Predictive biomarker; Sandwich-cultured rat hepatocytes; Steatosis