کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2569022 1128504 2012 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Gender-specific reduction of hepatic Mrp2 expression by high-fat diet protects female mice from ANIT toxicity
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
Gender-specific reduction of hepatic Mrp2 expression by high-fat diet protects female mice from ANIT toxicity
چکیده انگلیسی

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 4 weeks. 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.


► High-fat diet decreases hepatic Mrp2 expression only in female but not in male mice.
► HFD significantly reduces early-phase biliary ANIT excretion in female mice.
► HFD protects female mice against ANIT-induced liver injury.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology and Applied Pharmacology - Volume 261, Issue 2, 1 June 2012, Pages 189–195
نویسندگان
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