Abstract
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 (ABC) 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, ABCC4–5, ABCB1, and ABCG2 were found with NAFLD progression, whereas 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 in which the transporter appears to be internalized away from the canalicular membrane. This correlated with a preferential shift in the molecular mass of ABCC2 from 200 to 180 kDa 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, which may have profound effects on the ability of patients with NASH to eliminate drugs in an appropriate manner.
Footnotes
This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK068039]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES006694]; the National Institutes of Health National Center for Complementary and Alternative Medicine [Grant AT002842]; and the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant HD062489]. The Liver Tissue Cell Distribution System was sponsored by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Contract N01-DK70004/HHSN267200700004C].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.041012.
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The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- NAFLD
- nonalcoholic fatty liver disease
- NASH
- nonalcoholic steatohepatitis
- ABC
- ATP-binding cassette
- FFPE
- formalin-fixed, paraffin-embedded
- IHC
- immunohistochemical
- ADR
- adverse drug reaction
- CAR
- constitutive androstane receptor
- Nrf2
- NF-E2-related factor 2.
- Received June 2, 2011.
- Accepted August 30, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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