Differential Expression of Mouse Hepatic Transporter Genes in Response to Acetaminophen and Carbon Tetrachloride

Abstract

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.

Altered Pharmacokinetics of Daunorubicin in Rats with CCl4-Induced Hepatic Injury

“…The dysregulated redox status, in turn, activated adaptive mechanism to change the expression of hepatic transporters and metabolizing enzymes as well as detoxication genes. This coordinated regulation altered the expression to limit the accumulation of chemicals within the hepatocyte (i.e., in general, decreased hepatic uptake and increased canalicular efflux) (33,35), which is consistent with our results and implicates altered hepatic function and pharmacokinetics of drugs.…”

“…Moreover, CCl 4 , along with acetaminophen and alcohol, has been classically used in rodent models to investigate mechanisms of hepatotoxicity relevant to human exposure (35). Drug or chemicalinduced liver injury accounted for more than 50% of all cases of acute liver failure in the United States from 1997 to 2002 (36).…”

“…Therefore, in patients with chemical or drug induced hepatotoxicity, adjustment of dosage regimens for drugs that are substrates of these transporters or metabolizing enzymes would be needed (35,37), with particular care on that functional changes of transporters are multidirectional as a function of time after the hepatotoxicity induction (15).…”

Alteration of Hepatic but Not Renal Transporter Expression in Diet-Induced Obese Mice

“…Probe sets for mouse Abcc1-6, Oat1 and 2, Oct1 and 2, and Slco1a1, 1a4, 1b2, 1a6, and 2b1 have been described previously (Cherrington et al, 2003;Buist and Klaassen, 2004;Aleksunes et al, 2005;Cheng et al, 2005a,b). Oligonucleotide probe sets required for the assay were graciously donated by Dr. Curtis Klaassen.…”

Differential Regulation of Hepatic Transporters in the Absence of Tumor Necrosis Factor-α, Interleukin-1β, Interleukin-6, and Nuclear Factor-κB in Two Models of Cholestasis

“…Probe sets for mouse Oatp1,2,4,5,9,11,12,and 14;Oat2 and 3;Ntcp;Bsep; and 9 were used as described previously (Buist and Klaassen, 2004;Aleksunes et al, 2005;Cheng et al, 2005;Maher et al, 2005). The probe set for mouse Mdr1b is described in Table 1.…”