Document Detail


Gender-specific reduction of hepatic Mrp2 expression by high-fat diet protects female mice from ANIT toxicity.
MedLine Citation:
PMID:  22521610     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Emerging evidence suggests that feeding a high-fat diet (HFD) to rodents affects the expression of genes involved in drug transport. However, gender-specific effects of HFD on drug transport are not known. The multidrug resistance-associated protein 2 (Mrp2, Abcc2) is a transporter highly expressed in the hepatocyte canalicular membrane and is important for biliary excretion of glutathione-conjugated chemicals. The current study showed that hepatic Mrp2 expression was reduced by HFD feeding only in female, but not male, C57BL/6J mice. In order to determine whether down-regulation of Mrp2 in female mice altered chemical disposition and toxicity, the biliary excretion and hepatotoxicity of the Mrp2 substrate, α-naphthylisothiocyanate (ANIT), were assessed in male and female mice fed control diet or HFD for 4weeks. ANIT-induced biliary injury is a commonly used model of experimental cholestasis and has been shown to be dependent upon Mrp2-mediated efflux of an ANIT glutathione conjugate that selectively injures biliary epithelial cells. Interestingly, HFD feeding significantly reduced early-phase biliary ANIT excretion in female mice and largely protected against ANIT-induced liver injury. In summary, the current study showed that, at least in mice, HFD feeding can differentially regulate Mrp2 expression and function and depending upon the chemical exposure may enhance or reduce susceptibility to toxicity. Taken together, these data provide a novel interaction between diet and gender in regulating hepatobiliary excretion and susceptibility to injury.
Authors:
Bo Kong; Iván L Csanaky; Lauren M Aleksunes; Meghan Patni; Qi Chen; Xiaochao Ma; Hartmut Jaeschke; Scott Weir; Melinda Broward; Curtis D Klaassen; Grace L Guo
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-04-11
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  261     ISSN:  1096-0333     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-21     Completed Date:  2012-07-23     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  189-95     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Affiliation:
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
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MeSH Terms
Descriptor/Qualifier:
1-Naphthylisothiocyanate / toxicity*
Animals
Bile / drug effects
Diet, High-Fat*
Female
Liver / drug effects*,  metabolism
Male
Mice
Mice, Inbred C57BL
Multidrug Resistance-Associated Proteins / genetics*
Sex Characteristics
Grant Support
ID/Acronym/Agency:
AA12916/AA/NIAAA NIH HHS; DK070195/DK/NIDDK NIH HHS; DK081343/DK/NIDDK NIH HHS; ES-09649/ES/NIEHS NIH HHS; P20-RR021940/RR/NCRR NIH HHS; R01 DK081343/DK/NIDDK NIH HHS; R56 DK090036/DK/NIDDK NIH HHS; RR-0291940/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Multidrug Resistance-Associated Proteins; 0/multidrug resistance-associated protein 2; 551-06-4/1-Naphthylisothiocyanate
Comments/Corrections

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