Differential expression of mouse hepatic transporter genes in response to acetaminophen and carbon tetrachloride.
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 microl/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 microl/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.
Aleksunes
Lauren M
LM
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, USA. manautou@uconnvm.uconn.edu
Slitt
Angela M
AM
Cherrington
Nathan J
NJ
Thibodeau
Michael S
MS
Klaassen
Curtis D
CD
Manautou
José E
JE
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D051547:Heme Oxygenase-1; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D027361:Organic Anion Transporters / Q000235:genetics*
D000082:Acetaminophen; D002251:Carbon Tetrachloride; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase; D027361:Organic Anion Transporters; C496542:Hmox1 protein, mouse; C491732:Nqo1 protein, mouse