title: Modeling human nonalcoholic steatohepatitis-associated changes in drug transporter expression using experimental rodent models.
abstract: Nonalcoholic fatty liver disease is a prevalent form of chronic liver disease that can progress to the more advanced stage of nonalcoholic steatohepatitis (NASH). NASH has been shown to alter drug transporter regulation and may have implications in the development of adverse drug reactions. Several experimental rodent models have been proposed for the study of NASH, but no single model fully recapitulates all aspects of the human disease. The purpose of the current study was to determine which experimental NASH model best reflects the known alterations in human drug transporter expression to enable more accurate drug disposition predictions in NASH. Both rat and mouse NASH models were used in this investigation and include the methionine and choline deficient (MCD) diet model, atherogenic diet model, ob/ob and db/db mice, and fa/fa rats. Pathologic scoring evaluations demonstrated that MCD and atherogenic rats, as well as ob/ob and db/db mice, developed NASH. Liver mRNA and protein expression analyses of drug transporters showed that in general, efflux transporters were induced and uptake transporters were repressed in the rat MCD and the mouse ob/ob and db/db models. Lastly, concordance analyses suggest that both the mouse and rat MCD models as well as mouse ob/ob and db/db NASH models show the most similarity to human transporter mRNA and protein expression. These results suggest that the MCD rat and mouse model, as well as the ob/ob and db/db mouse models, may be useful for predicting altered disposition of drugs with similar kinetics across humans and rodents.
authors.affiliation: University of Arizona, Department of Pharmacology and Toxicology, Tucson, Arizona.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Canet
authors.forename: Rhiannon N
authors.initials: RN
authors.lastname: Hardwick
authors.forename: April D
authors.initials: AD
authors.lastname: Lake
authors.forename: Anika L
authors.initials: AL
authors.lastname: Dzierlenga
authors.forename: John D
authors.initials: JD
authors.lastname: Clarke
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Cherrington
mesh_terms: D000818:Animals; D002796:Choline Deficiency / Q000150:complications; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics; D004036:Diet, Atherogenic / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D027361:Organic Anion Transporters; D004364:Pharmaceutical Preparations; D008715:Methionine