* 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
1 To whom correspondence should be addressed at Toxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, 372 Fairfield Rd. U-2092, Storrs, CT 06269. Fax: 8604864998. E-mail: manautou{at}uconnvm.uconn.edu.
Received October 6, 2004; accepted October 8, 2004
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ABSTRACT |
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Key Words: acetaminophen; carbon tetrachloride; hepatotoxicity; transporters; Mrp4.
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INTRODUCTION |
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Importantly, chemical-induced liver injury impairs hepatobiliary function and results in altered disposition of xenobiotics. In turn, clinicians are required to adjust dosages and dosing intervals of pharmaceuticals to compensate for reduced hepatic function in patients. Altered drug disposition in patients with liver damage has been attributed to reduced hepatic albumin production, altered protein plasma binding, poor hepatic blood flow, and altered expression and activity of Phase I and II drug-metabolizing enzymes (Verbeeck and Horsmans, 1998). However, little is known about changes in transport processes during hepatic injury, which may contribute to altered disposition and the necessity for adjustments in drug therapy.
Extraction of compounds from portal blood and subsequent excretion of the parent compound and its metabolites occurs via basolateral and canalicular transporters in hepatocyte plasma membranes (Arrese and Accatino, 2002). Constitutively expressed uptake carriers, such as organic anion-transporting polypeptides (Oatps) and the sodium/taurocholate-cotransporting polypeptide (Ntcp), transport xenobiotics and bile acids across the basolateral membrane into the hepatocyte. Subsequent excretion of these chemicals is mediated by numerous export transporters, including multidrug resistance proteins (Mdrs) also known as p-glycoprotein (Pgp), multidrug resistance-associated proteins (Mrps), bile salt export pump (Bsep), and breast cancer resistance protein (Bcrp). Canalicular transporters, such as Mrp2, Mdrs, Bcrp, and Bsep, are responsible for excretion of compounds and their metabolites from hepatocytes into bile, whereas basolateral transporters, such as Mrp 1, 36, are thought to mediate efflux of chemicals from hepatocytes into blood.
Despite the high incidence of drug-induced liver injury in the United States, little is known about the expression of hepatic membrane transporters and their influence on xenobiotic disposition in individuals with acute liver damage. Limited data demonstrate altered expression of xenobiotic transporters during chemical-induced hepatotoxicity. Administration of CCl4 results in reduced expression of rat Ntcp, Oatp1a1 [previously called Oatp1 (Slc21a1)], and Oatp1a4 [previously called Oatp2 (Slc21a5)] mRNA, with no change in levels of Mrp2, Bsep, and Oatp1b2 [previously called Oatp4 (Slc21a10)] (Geier et al., 2002). Altered canalicular clearance of substrates for Pgp, Bsep, and Mrp2 was observed in hepatic membrane preparations from rats given CCl4 (Song et al., 2003
). Treatment with APAP results in the up-regulation of canalicular Mrp2 and Pgp protein in rat liver (Ghanem et al., 2004
). Additionally, administration of the hepatotoxicant bromobenzene increases the hepatic expression of Mrp1-3 mRNA in rat liver (Heijne et al., 2004
).
In order to investigate the regulation of transporter expression following chemical-induced liver injury, mice were injected with doses of APAP (200400 mg/kg) or CCl4 (1025 µl/kg) that resulted in varying degrees of hepatic damage over a 48-h time period. The analysis of transporter expression was extended to include numerous transporters not previously investigated during chemical-induced liver injury in rats. The inclusion of three time points (6, 24, and 48 h) for analysis of transporter expression enabled comprehensive characterization of temporal changes in relation to injury and recovery. The two hepatotoxicants were studied due to similarities and differences in their mechanisms of toxicity. Notably, APAP-induced hepatotoxicity has been associated with covalent adduct formation, depletion of cellular antioxidants such as glutathione, as well as generation of reactive oxygen and nitrogen species. Conversely, CCl4-mediated liver injury is generally characterized by formation of lipid peroxides and altered redox status. In this study, hepatotoxic doses of APAP and CCl4 resulted in the coordinated up-regulation of hepatic oxidative stress and efflux transport genes, as well as the concomitant reduction of uptake transporters.
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MATERIALS AND METHODS |
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Treatment of animals. Male C57BL/6 J mice, aged 1012 weeks old, were purchased from Jackson Laboratories (Bar Harbor, ME). Mice acclimated 1 week upon arrival. Animals were housed in a 12-h dark/light cycle, temperature- and humidity-controlled environment. The mice were fed laboratory rodent diet (No. 5001, PMI Feeds, St. Louis, MO) ad libitum. APAP was dissolved in 50% propylene glycol:water. CCl4 was diluted in corn oil. Groups of mice (n = 37) were administered APAP (200, 300, or 400 mg/kg, 10 ml/kg, ip), CCl4 (10 or 25 µl/kg, 5 ml/kg, ip) or the respective vehicle control. The doses of APAP and CCl4 were selected in order to achieve mild to moderate, but not overt toxicity. Livers and plasma were collected 6, 24, or 48 h after APAP or CCl4 administration. Portions of each liver were removed for fixation in formalin. The remaining liver tissue was removed and snap-frozen in liquid nitrogen. Frozen tissues were stored at 80°C until assayed. All animal studies were conducted in accordance with National Institutes of Health standards and the Guide for the Care and Use of Laboratory Animals.
Alanine aminotransferase (ALT) activity. Plasma ALT activity was determined as a biochemical indicator of hepatocellular necrosis using Infinity ALT Liquid Stable Reagent (Thermotrace, Melbourne, Australia) according to the manufacturer's protocol.
Histopathology. Liver samples were fixed in 10% neutral-buffered formalin prior to routine processing and paraffin embedding. Liver sections (5 µm in thickness) were stained with hematoxylin and eosin. Sections were examined by light microscopy for the presence and severity of hepatocellular degeneration and necrosis. Centrilobular liver injury was scored using a grading system described previously (Manautou et al., 1994). Histopathology scoring was as follows: no injury = grade 0; minimal injury involving single to few hepatocytes = grade 1; mild injury affecting 1025% of hepatocytes = grade 2; moderate injury affecting 2540% of hepatocytes = grade 3; marked injury affecting 4050% of hepatocytes = grade 4; or severe injury affecting more than 50% of hepatocytes = grade 5.
RNA extraction. Total tissue RNA was extracted using RNAzol B reagent (Tel-Test Inc., Friendswood, TX) according to the manufacturer's protocol. RNA pellets were resuspended in diethyl pyrocarbonate-treated deionized water. RNA samples were analyzed by agarose gel electrophoresis, and integrity was confirmed by visualization of intact 18S and 28S rRNA under ultraviolet light.
Branched DNA signal amplification (bDNA) assay. Mouse Mrp1, 2, 3, 4, 5, 6, Bcrp, Oatp1a1, 1a4, 1b2, Ntcp, Nqo1, and Ho-1 mRNA were measured using the branched DNA signal amplification assay (Quantigene® High Volume bDNA Signal Amplification Kit, Genospectra, Fremont, CA) according to the method of Hartley and Klaassen (Hartley and Klaassen, 2000). Mouse gene sequences of interest were acquired from GenBank. Multiple oligonucleotide probe sets [capture extender (CE), label extender (LE), and blocker (BL) probes] were designed using Probe Designer software version 1.0 (Bayer Corp. Emeryville, CA), to be highly specific to a single mRNA transcript. Probesets for mouse Mrp1, 2, 4, 5, 6, Bcrp, Oatp1a1, 1a4, 1b2, Ntcp, Nqo1, and Ho-1 are listed in Supplementary Table 1. Probes to detect mouse Mrp3 have been previously described (Cherrington et al. 2003
). All oligonucleotide probes were designed with a melting temperature of approximately 63°C. This enabled stringent hybridization conditions to be held constant (i.e., 53°C) during each hybridization step for each oligonucleotide probe set. Each probe designed in ProbeDesigner was submitted to the National Center for Biotechnological Information for nucleotide comparison by the basic local alignment search tool (BLASTn) to ensure minimal cross-reactivity with other mouse sequences. Oligonucleotides with a high degree of similarity to other mouse gene transcripts were eliminated from the design. Probes were synthesized by QIAGEN Operon (Alameda, CA). Briefly, 10 µl of sample RNA (1 µg/µl) were added to each well of a 96-well plate containing 50 µl of capture hybridization buffer and 100 µl of diluted probe set. Total RNA was allowed to hybridize to probe sets overnight at 53°C. Subsequent hybridization steps were carried out according to the manufacturer's protocol, and luminescence was measured with a Quantiplex® 320 bDNA Luminometer interfaced with Quantiplex® Data Management Software version 5.02. The luminescence for each well was reported as relative light units (RLU) per 10 µg total RNA.
Statistical analysis. Data from control animals at 6, 24, and 48 h were pooled and designated 0 h for gene expression analysis. No changes in basal transporter expression from control livers were seen over the 48 h time period. Quantitative results were expressed as means ± standard error of the mean (n > 3). Data were analyzed using one-way analysis of variance (ANOVA) followed by Duncan's multiple range test (p < 0.05).
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RESULTS |
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DISCUSSION |
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Similarly, CCl4 treatment reduces the expression of Oatp1a1, Oatp1a4, and Ntcp in rat liver. More recent work shows the up-regulation of Mrp2 and Pgp expression and function following APAP treatment of rats (Ghanem et al., 2004). The work presented in this manuscript more comprehensively documents the down-regulation of mouse uptake carriers (Oatp and Ntcp) and up-regulation of Mrp efflux and stress (Ho-1 and Nqo1) genes. Collectively, these data support the hypothesis that the liver alters gene expression following injury to limit the accumulation of chemicals within the hepatocyte.
To date, this is the first study that documents a marked induction of hepatic Mrp4 transcript in mouse liver. Limited data exists regarding the potential role of Mrp4 in liver injury. Mrp4 mRNA is up-regulated in bile duct-ligated mice (Wagner et al., 2003), although to a much lesser extent (three-fold). Mrp4 substrates include nucleotide chemicals, including cyclic AMP and GMP, prostaglandin E1 and E2, as well as some HIV antiviral drugs (Borst et al., 2000
; Reid et al., 2003
; Sampath et al., 2002
). Additionally, Mrp4 transports sulfated compounds, including the steroid, dehydroepiandrosterone 3-sulphate (Assem et al., 2004
). The coordinated transcriptional regulation of Mrp4 and sulfotransferase 2a1 has been reported to occur through constitutive androstane receptor (CAR)-mediated signaling pathways (Assem et al., 2004
). Interestingly, modulation of CAR alters susceptibility of mice to APAP-induced hepatotoxicity (Zhang et al., 2002
). Therefore, activation of CAR during liver injury may represent one mechanism contributing to the up-regulation of Mrp4 in these studies.
Although the up-regulation of efflux and down-regulation of uptake transporters during hepatotoxicity appears to represent a general pattern in response to injury, some of the changes were specific to either APAP or CCl4. In some instances, different isoforms of Mrp and Oatp were altered by APAP (Mrp3, Oatp1b2) and CCl4 (Mrp1, Oatp1a1, Oatp1b2), while similar changes in Mrp2, Mrp4, Oatp1a4 were seen by both. This differential regulation may reflect the different pathogenic and transcriptional pathways elicited by APAP and CCl4. For example, down-regulation of Oatp1b2 and Ntcp during CCl4-induced hepatotoxicity may represent an attempt to limit influx of potentially harmful bile acids. On the contrary, the increase in Mrp1 and Mrp2 expression in response to CCl4 may enable efficient removal of the lipid peroxide 4-hydroxynonenal generated during injury (Reichard et al., 2003; Renes et al., 2000
).
It should be noted that APAP and CCl4 are not thought to be substrates for uptake transporters and instead appear to enter the hepatocyte by diffusion (McPhail et al., 1993). The induction of Mrps may be an attempt by the hepatocyte to remove residual APAP metabolites, such as APAP-glucuronide, which is a substrate of Mrp2 and Mrp3 (Chen et al., 2003
; Slitt et al., 2003
; Xiong et al., 2002
). It is presently unknown if Mrp4 transports APAP-glucuronide. Based upon the temporal up-regulation of Mrp genes at 24 and 48 h in this study, these changes would be futile, because these conjugates are efficiently cleared in mice during the first 24 h (Wong et al., 1981
). Instead, these changes in transport may represent an attempt to better dispose of these metabolites upon a second challenge with APAP.
In addition to the transporter isoform-specific changes, the magnitude of altered expression differs between APAP and CCl4-treated mice. Presently, it is difficult to determine whether the marked increase (37-fold) in Mrp4 expression following CCl4 treatment compared to the moderate increase (5-fold) with APAP is related to differences in the mechanisms of injury, intrinsic xenobiotic properties, or the extent of hepatic injury achieved in these studies. Further analysis of additional hepatotoxicants, such as bromobenzene and chloroform, as well as higher doses of APAP may address this discrepancy in the magnitude of change in Mrp4 expression between the two hepatotoxicity models.
Inclusion of Ho-1 and Nqo1 in our analysis may offer additional insight into the regulatory mechanisms underlying the observed changes in transporter expression. Inducible expression of Ho-1 in mouse liver is in part regulated by cytokine signaling, including interleukin-6 (IL-6) (Masubuchi et al., 2003). Studies with IL-6 null mice demonstrate a role for IL-6 in the regulation of Mrp2, Mrp3, and Ntcp expression following lipopolysaccharide treatment (Siewert et al., 2004
). Similarly, exogenous administration of IL-6 reduces murine expression of Mrp2, Oatp1a1, and Oatp1a4 mRNA (Hartmann et al., 2002
). The critical role of IL-6 extends to modulation of hepatotoxicity, proliferation, and repair pathways in response to APAP and CCl4 (James et al., 2003
; Masubuchi et al., 2003
). Coordinated regulation of both detoxication and transport genes through IL-6 signaling during liver toxicity may represent a recovery mechanism by the injured hepatocyte.
Nuclear transcription factor-E2 p45-related factor 2 (Nrf2) is a transcription factor that regulates expression of multiple hepatic detoxification and stress genes including Nqo1, Ho-1, and glutathione-S-transferase during oxidative stress. Mice deficient in Nrf2 are more sensitive to the toxic effects of APAP (Chan et al., 2001; Enomoto et al., 2001
). The enhanced sensitivity of Nrf2-deficient mice results, in part, from impaired compensatory up-regulation of these detoxication genes. Interestingly, Nrf2 is required for the constitutive and inducible expression of Mrp1 in mouse embryo fibroblasts (Hayashi et al., 2003
). Further investigation is necessary to determine the potential role of Nrf2 in regulating hepatic membrane transporters in mice.
This study comprehensively characterizes the temporal and dose-related changes in transporter expression during chemical-induced hepatotoxicity. A better understanding of this altered expression is necessary to address the contribution of transport mechanisms to the impaired hepatic clearance of xenobiotics during liver injury. Clinical management of patients with drug-induced liver disease should consider the role of altered transporter expression when selecting doses and dosing regimens for administration of pharmaceuticals.
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SUPPLEMENTARY DATA |
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ACKNOWLEDGMENTS |
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