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Differential expression of mouse hepatic transporter genes in response to acetaminophen and carbon tetrachloride

Lauren M Aleksunes1, Angela M Slitt, Nathan J Cherrington

  • 1Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, USA. manautou@uconnvm.uconn.edu

Toxicological Sciences : an Official Journal of the Society of Toxicology
|October 22, 2004
PubMed

Insights

Hepatotoxicants like acetaminophen and carbon tetrachloride alter liver gene expression. Uptake transporters decreased while detoxifying enzymes and efflux transporters increased, potentially protecting liver cells from damage.

Area of Science:

  • Hepatotoxicity and Xenobiotic Metabolism
  • Molecular Toxicology
  • Drug Metabolism and Transport

Background:

  • Drug-metabolizing enzymes and membrane transporters are crucial for eliminating foreign compounds (xenobiotics).
  • Liver injury can result from exposure to hepatotoxic substances like acetaminophen and carbon tetrachloride.
  • Understanding how these toxins affect gene expression is vital for predicting and mitigating liver damage.

Purpose of the Study:

  • To investigate changes in mRNA expression of key detoxifying enzymes and membrane transporters in mouse liver following exposure to acetaminophen (APAP) and carbon tetrachloride (CCl4).
  • To correlate these gene expression changes with indicators of liver injury.

Main Methods:

  • Male C57BL/6 J mice were administered varying doses of APAP or CCl4.
  • Liver and plasma samples were collected at 6, 24, and 48 hours post-administration.
  • Assessed alanine aminotransferase (ALT) activity, performed histopathological analysis, and quantified mRNA levels of specific genes (Ho-1, Nqo1, Oatp, Ntcp, Mrp1-6) using branched DNA signal amplification.

Main Results:

  • Hepatotoxic doses of APAP and CCl4 significantly increased mRNA levels of heme oxygenase-1 (Ho-1) and NAD(P)H quinone oxidoreductase-1 (Nqo1).
  • Expression of uptake transporters, including organic anion-transporting polypeptides (Oatp1a1, 1a4) and sodium/taurocholate-cotransporting polypeptide (Ntcp), was reduced.
  • mRNA levels for multidrug resistance-associated proteins (Mrp1-4) were elevated, with a notable surge in Mrp4 following high-dose APAP and CCl4 exposure.

Conclusions:

  • Acetaminophen and carbon tetrachloride induce coordinated changes in the expression of genes involved in xenobiotic transport and detoxification during liver injury.
  • Reduced expression of uptake transporters, coupled with increased detoxifying enzymes and efflux transporters, may represent a protective mechanism to limit hepatocyte damage.

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