RT Journal Article
SR Electronic
T1 Variations in ABC-Transporter Regulation during the Progression of Human Nonalcoholic Fatty Liver Disease
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.111.041012
DO 10.1124/dmd.111.041012
A1 Rhiannon N Hardwick
A1 Craig D Fisher
A1 Mark J Canet
A1 George L Scheffer
A1 Nathan J Cherrington
YR 2011
UL http://dmd.aspetjournals.org/content/early/2011/08/30/dmd.111.041012.abstract
AB Hepatic transport protein expression can have a profound effect on the uptake and efflux of drugs in the overall process of drug management. Transporters located on the sinusoidal and canalicular membranes of hepatocytes regulate the efflux of drugs and metabolites into blood and bile, respectively. Changes in the expression or function of these transporters during liver disease may lead to a greater risk of adverse drug reactions. Nonalcoholic fatty liver disease (NAFLD) is a progressive condition encompassing the relatively benign steatosis and the more severe, inflammatory state of nonalcoholic steatohepatitis (NASH). Here, we present an analysis of the effect of NAFLD progression on the major ATP-binding cassette efflux transport proteins ABCC1-6, ABCB1, and ABCG2. Human liver samples diagnosed as normal, steatotic, NASH (fatty), and NASH (not fatty) were analyzed. Increasing trends in mRNA expression of ABCC1, 4-5, ABCB1, and ABCG2 were found with NAFLD progression, while protein levels of all transporters exhibited increasing trends with disease progression. Immunohistochemical staining of ABCC3, ABCB1, and ABCG2 revealed no alterations in cellular localization during NAFLD progression. ABCC2 staining revealed an alternative mechanism of regulation in NASH where the transporter appears to be internalized away from the canalicular membrane. This correlated to a preferential shift in the molecular weight of ABCC2 from 200kDa to 180kDa in NASH, which has been shown to be associated with a loss of glycosylation and internalization of the protein. These data demonstrate increased expression of multiple efflux transporters, as well as altered cellular localization of ABCC2 in NASH. Such alterations in efflux drug transporters may have profound effects on the ability of patients with NASH to eliminate drugs in an appropriate manner.