ToxSci Advance Access originally published online on October 20, 2004
Toxicological Sciences 2005 83(1):44-52; doi:10.1093/toxsci/kfi013
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Toxicological Sciences vol. 83 no. 1 © Society of Toxicology 2005; all rights reserved.
Differential Expression of Mouse Hepatic Transporter Genes in Response to Acetaminophen and Carbon Tetrachloride
* Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269; Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160; and Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721
Received October 6, 2004; accepted October 8, 2004
Drug-metabolizing enzymes and membrane transporters are responsible for the detoxication and elimination of xenobiotics from the body. The goal of this study was to identify alterations in mRNA expression of various transport and detoxication proteins in mouse liver after administration of the hepatotoxicants, acetaminophen or carbon tetrachloride. Therefore, male C57BL/6 J mice received acetaminophen (APAP, 200, 300, or 400 mg/kg, ip) or carbon tetrachloride (CCl4, 10 or 25 µl/kg, ip). Plasma and liver samples were collected at 6, 24, and 48 h for assessment of alanine aminotransferase (ALT) activity, total RNA isolation, and histopathological analysis of injury. Heme oxygenase-1 (Ho-1), NAD(P)H quinone oxidoreductase-1 (Nqo1), organic anion-transporting polypeptides (Oatp1a1, 1a4 and 1b2), sodium/taurocholate-cotransporting polypeptide (Ntcp), and multidrug resistance-associated protein (Mrp 1–6) mRNA levels in liver were determined using the branched DNA signal amplification assay. Hepatotoxic doses of APAP and CCl4 increased Ho-1 and Nqo1 mRNA levels by 22- and 2.5-fold, respectively, and reduced Oatp1a1, 1a4, and Ntcp mRNA levels in liver. By contrast, expression of Mrps 1–4 was increased after treatment with APAP and CCl4. Notably, a marked elevation of Mrp4 mRNA expression was observed 24 h after APAP 400 mg/kg (5-fold) and CCl4 25 µl/kg (37-fold). Collectively, these expression patterns suggest a coordinated regulation of both transport and detoxification genes during liver injury. This reduction in expression of uptake transporters, as well as enhanced transcription of detoxication enzymes and export transporters may limit the accumulation of potentially toxic products in hepatocytes.
Key Words: acetaminophen; carbon tetrachloride; hepatotoxicity; transporters; Mrp4.
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