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Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
(Received September 11, 2003; accepted July 29, 2004)
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Abstract |
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, interleukin (IL) 1ß, and IL-6 after LPS administration. For the dose-response study, LPS (1 mg/kg i.p.) produced a significant decrease in Oatp4 mRNA levels in TLR4-normal C3H/OuJ mice, and higher doses produced slightly greater decreases. However, none of the doses of LPS examined significantly decreased Oatp4 mRNA levels in TLR4-mutant C3H/HeJ mice. For the time-response study, LPS (5 mg/kg i.p.) produced a rapid decrease in Oatp4 mRNA levels in TLR4-normal C3H/OuJ mice. The maximal decrease in Oatp4 mRNA levels (80%) was observed 12 h after LPS administration and returned to control levels thereafter. In contrast, LPS did not produce a significant decrease in Oatp4 mRNA levels at any time in TLR4-mutant C3H/HeJ mice. These findings demonstrate that LPS decreases Oatp4 mRNA levels in mice, and the decrease is mediated through TLR4.
). The liver is not only a major target organ of LPS toxicity, but also a primary site for the uptake and clearance of microbial products (Tanikawa et al., 1998). It has been shown that LPS alters hepatic gene expression, leading to up-regulation of some acute phase proteins (Baumann and Gauldie, 1994) and down-regulation of some hepatic transport proteins, such as Na+/taurocholate-cotransporting polypeptide (Ntcp), organic anion-transporting polypeptide (Oatp) 1, Oatp2, multidrug resistance-associated protein 2 (Mrp2), and bile salt export pump (Bsep) (Trauner et al., 1998; Denson et al., 2000; Hartmann et al., 2002), as well as drug-metabolizing enzymes (Beigneux et al., 2002). However, the effect of LPS on Oatp4 remains to be determined.
Sepsis is frequently associated with cholestasis (Caruana et al., 1982), which is characterized by impairment of hepatic transport of bile acids and other organic anions. After LPS administration, Na+-independent uptake of the organic anion sulfobromophthalein (BSP) across hepatic sinusoidal membranes was reduced by 40 to 55% (Bolder et al., 1997). An alternative model of sepsis, cecal ligation and puncture, is known to reduce rat Oatp4 mRNA levels by 80% (Kakyo et al., 1999). It has been shown that Oatp4, the most abundant Oatp in rat liver, mediates hepatic uptake of bile acids and BSP in a Na+-independent manner (Kakyo et al., 1999; Cattori et al., 2000; Li et al., 2002). Therefore, it is reasonable to hypothesize that LPS may decrease Oatp4 mRNA levels.
Cell surface Toll-like receptors (TLRs) are known to be involved in innate immune recognition and cellular activation in response to various infections. Members of the TLR family are transmembrane proteins containing repeated leucine-rich motifs in their extracellular domains, and a cytoplasmic TIR (Toll/IL-1 receptor) domain. Mammalian Toll-like receptor 4 (TLR4) has been evolutionarily conserved, presumably to transduce the extracellular LPS signal across the plasma membrane (Poltorak et al., 1998; Rock et al., 1998; Chow et al., 1999). In blood, LPS binds to a protein called LPS-binding protein. The LPS-binding protein-LPS complex is then recognized and bound by TLR4. However, for optimal response to LPS, the TLR4 needs supportive extracellular molecules such as MD-2 and CD14 (Ulevitch and Tobias, 1999; Shimazu et al., 1999). After dimerization of TLR4, the TIR domain of TLR4 engages myeloid differentiation factor 88 (MyD88)-adaptor-like protein (MyD88/Mal) through homophilic binding of the TIR domain of MyD88/Mal. MyD88/Mal then engages IL-1 receptor-associated kinase, which is then autophosphorylated. TNF receptor-associated factor 6 then interacts with IL-1 receptor-associated kinase. Evolutionarily conserved signaling intermediate in Toll pathways bridges TNF receptor-associated factor 6 and mitogen-activated protein kinase kinase 1, leading to phosphorylation and degradation of the inhibitor of nuclear factor of the 
-enhancer in B cells-inhibitory protein (I-B). Nuclear factor of the -enhancer in B cells is then released and translocated to the nucleus, where it regulates the expression of target genes, such as TNF-, IL-1ß, and IL-6 (Medzhitov et al., 1997; Hoshino et al., 1999).
A single locus (Lps) on chromosome 4 is responsible for the defective response to LPS (Watson et al., 1978), and the defect of the C3H/HeJ strain is due to the homozygosity of Lpsd (Sultzer, 1968; Rosenstreich et al., 1978). In contrast, the C3H/OuJ strain (Lpsn) exhibits a vigorous response to LPS, despite having diverged from the same stock as C3H/HeJ mice. Poltorak et al. (1998) showed that the Lpsd locus contained a missense mutation (P712H) in the third exon of the Tlr4 of C3H/HeJ mice. Despite the missense mutation, C3H/HeJ mice are developmentally and immunologically normal, except for their inability to respond to LPS and to counter the infection of Gram-negative bacteria. The importance of TLR4 for LPS signaling was further confirmed by the targeted disruption of the Tlr4, indicating that the defect can be reversed by reintroducing a normal copy of the gene in macrophages derived from TLR4-/- mice (Hoshino et al., 1999). Taken together, these genetic studies have established that TLR4 is an important signal-transducing component of the LPS receptor complex.
The present study was designed to determine 1) whether LPS treatment decreases Oatp4 mRNA levels in mice, 2) whether C3H/HeJ mice, containing a missense mutation of the Tlr4, still exhibit the LPS effect on Oatp4 mRNA levels, and 3) whether the possible decrease in Oatp4 mRNA levels following LPS administration is associated with LPS-stimulated production of TNF-, IL-1ß, and IL-6 in serum using TLR4-mutant C3H/HeJ and TLR4-normal C3H/OuJ mice.
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Materials and Methods |
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-irradiated). LPS was dissolved in a volume of 10 ml of saline/kg of body weight for i.p. injection. In our preliminary studies, we did not find any evidence of effects of saline injection or circadian variation of Oatp4 mRNA levels. For the dose-response study, C3H/OuJ and C3H/HeJ mice were injected i.p. with 0, 1, 2.5, 6, or 15 mg of LPS/kg of body weight (n = 5/strain/dose). Livers were excised 16 h after LPS administration. For the time-response study, LPS (5 mg/kg body weight, i.p.) was used. Livers were excised and blood was collected by decapitation at 0, 1.5, 3, 6, 12, 16, 24, and 48 h after LPS administration (n = 5/strain/time). Controls for the time-response study were the animals that were treated with LPS and sacrificed at 0 h. Livers were flash-frozen in liquid nitrogen and stored at -80°C until further use. Blood samples were allowed to clot for 2 h at room temperature or overnight at 2-8°C before centrifuging for 20 min at approximately 2000g. Sera were then removed and stored at -20°C. RNA Isolation. Total RNA was isolated from liver using RNAzol B reagent (Tel-Test Inc., Friendswood, TX) according to the manufacturer's protocol. The concentration of total RNA in each sample was quantified spectrophotometrically at 260 nm. Integrity of each RNA sample was evaluated by form-aldehyde-agarose gel electrophoresis before analysis. Purity of each RNA sample was accepted if A260/A280 > 1.8.
Branched DNA (bDNA) Assays. Oatp4 mRNA levels in liver were determined by the quantitative branched DNA signal amplification assay (QuantiGene bDNA Signal Amplification Kit; Bayer Corp.-Diagnostics Div. (Tarrytown, NY) (Hartley and Klaassen, 2000). Mouse Oatp4 gene sequence was accessed from GenBank (accession number AB031959
[GenBank]
). A multiple oligonucleotide probe set (capture probes, label probes, and a blocker probe) specific to the mouse Oatp4 transcript (Table 1) was designed using ProbeDesigner software, version 1.0 (Bayer Corp.-Diagnostics Div.). Each probe developed in ProbeDesigner was submitted to the National Center for Biotechnology Information (Bethesda, MD) for nucleotide comparison by the basic local alignment search tool to ensure minimal cross-reactivity with other known mouse sequences and expressed sequence tags. Any oligonucleotide with a high degree of similarity (>80%) to other mouse gene transcripts was eliminated from the design. Probes were designed with a melting temperature of approximately 63°C, enabling hybridization conditions to be held constant (i.e., 53°C) during each hybridization step. All probes were synthesized by QIAGEN Operon (Alameda, CA) and obtained desalted and lyophilized. Total RNA (1 µg/µl) was added to each well (10 µl/well) of a 96-well plate, containing 50 µl of capture hybridization buffer and 50 µl of each diluted probe set, and allowed to hybridize to the probe set overnight at 53°C. Subsequent hybridization steps were carried out according to the manufacturer's protocol. Luminescence from 96-well plates was analyzed with a Quantiplex 320 bDNA luminometer interfaced with Quantiplex data management software, version 5.02 (Bayer Corp.-Diagnostics Div.). The luminescence for each well was reported as relative light units per 10 µg of total RNA. The sample relative light unit values were normalized by that of glyceraldehyde-3-phosphate dehydrogenase.
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Enzyme-Linked Immunosorbent Assay (ELISA). The concentrations of immunoreactive TNF-, IL-1ß, and IL-6 in serum were determined by ELISA according to the manufacturer's protocol (R&D Systems, Minneapolis, MN).
Statistical Analysis. Differences between control and treatment groups were determined by analysis of variance, followed by Duncan's multiple range post hoc test. Statistical significance was considered at p < 0.05.
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Results |
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; Green et al., 1996; Moseley et al., 1996; Bolder et al., 1997; Trauner et al., 1997). However, the present study established both dose- and time-response relationships between LPS and Oatp4 mRNA levels because the effect of LPS on Oatp4 has not been previously reported. The effect of LPS on Oatp4 mRNA levels was determined in livers of C3H/OuJ and C3H/HeJ mice after a single i.p. injection of 0, 1, 2.5, 6, or 15 mg of LPS/kg. A low dose of LPS (1 mg/kg) caused a significant decrease in Oatp4 mRNA levels in TLR4-normal C3H/OuJ mice, and higher doses produced similar or slightly greater decreases (Fig. 1). In TLR4-mutant C3H/HeJ mice, LPS (1 mg/kg) tended to decrease Oatp4 mRNA levels, but the decrease in Oatp4 mRNA levels was not statistically significant at any dose compared with TLR4-normal C3H/OuJ mice. As is apparent from Fig. 1, the levels of Oatp4 mRNA between C3H/OuJ and C3H/HeJ mice were quite different at 6 and 15 mg of LPS/kg. These results indicate that LPS caused a dose-dependent decrease in Oatp4 mRNA levels in TLR4-normal C3H/OuJ mice, but not in TLR4-mutant C3H/HeJ mice. The absence of significant difference at low doses, such as 2.5 mg of LPS/kg, was probably due to interanimal variability as well as LPS injection. Mice treated with LPS tend to eat or drink less, which affects liver metabolism. The minor decrease in Oatp4 mRNA level observed in C3H/HeJ mice after LPS treatment might also be due to the starvation effect. However, the response of TLR4-normal C3H/OuJ mice to a high dose of LPS overcomes the LPS stress, whereas the response of TLR4-mutant C3H/HeJ mice to a high dose of LPS does not. These results strongly demonstrate that the LPS effect on Oatp4 mRNA levels is mediated by TLR4.
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Time-Response Relationship between LPS on Oatp4 mRNA Levels in TLR4-Normal C3H/OuJ and TLR4-Mutant C3H/HeJ Mice. A dose of LPS (5 mg/kg i.p.) was selected to investigate time-related effect of LPS on Oatp4 mRNA levels. As shown in Fig. 2, LPS produced a relatively rapid and marked reduction of Oatp4 mRNA levels in livers of TLR4-normal C3H/OuJ mice. The maximal decrease (80%) in Oatp4 mRNA levels was observed 12 h after LPS administration and returned to control levels between 12 and 48 h. In TLR4-mutant C3H/HeJ mice, LPS tended to decrease Oatp4 mRNA, but the decrease was not statistically significant. As depicted in Fig. 2, differences in Oatp4 mRNA levels between C3H/OuJ and C3H/HeJ mice were apparent at 6, 12, and 16 h after LPS administration. These results indicate that LPS produced a time-dependent decrease in Oatp4 mRNA levels in TLR4-normal C3H/OuJ mice. Moreover, the LPS-induced decrease in Oatp4 mRNA levels was reversible.
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Time Course of Cytokine Concentrations in Serum of TLR4-Normal C3H/OuJ and TLR4-Mutant C3H/HeJ Mice after LPS Administration. LPS is a well known stimulant of cytokine synthesis, eliciting increased production of TNF-, IL-1ß, and IL-6 by monocytes. Among these cytokines, TNF- is thought to be the primary mediator of most effects produced by LPS. As shown in Fig. 3, the maximal concentration of TNF- in serum after LPS administration was much higher in TLR4-normal C3H/OuJ than in TLR4-mutant C3H/HeJ mice. After administration of LPS to TLR4-normal C3H/OuJ mice, TNF- reached a maximal concentration (3400 pg/ml) at 1.5 h and declined to the baseline by 12 h. In contrast, the maximal concentration of TNF- in serum of TLR4-mutant C3H/HeJ mice was only 230 pg/ml and returned to control values by 3 h after LPS administration.
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As shown in Fig. 4, serum IL-1ß reached a maximal concentration (381 pg/ml) 3 h after LPS administration to TLR4-normal C3H/OuJ mice and declined to control levels thereafter. In contrast, the maximal serum concentration of IL-1ß was 30 pg/ml and returned to control values by 6 h after LPS administration to TLR4-mutant C3H/HeJ mice.
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As shown in Fig. 5, the maximal serum concentration of IL-6 (23,300 pg/ml) was observed 3 h after LPS administration to TLR4-normal C3H/OuJ mice and then returned to near control levels by 12 h. In contrast, the LPS-stimulated IL-6 concentration in serum of TLR4-mutant C3H/HeJ mice was 1100 pg/ml and returned to control levels by 6 h after LPS administration.
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Discussion |
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), isolated hepatocytes (Whiting et al., 1995), and rat plasma membrane vesicles (Green et al., 1996; Moseley et al., 1996; Bolder et al., 1997) and have shown that LPS produces a decrease in bile flow, which is thought to be due to the down-regulation of the hepatic bile acid uptake transporter (e.g., Ntcp) and bile acid efflux transporters (e.g., Bsep, Mrp2). The hepatic uptake transporter Oatp4 is almost exclusively expressed in liver (Ogura et al., 2000; Li et al., 2002) and mediates Na+-independent transport of a variety of substrates, including bile acids and BSP, as well as other endogenous and exogenous compounds (Kakyo et al., 1999; Cattori et al., 2000). The present study clearly demonstrates that LPS down-regulates Oatp4, and therefore provides another possible mechanism underlying sepsis-associated cholestasis, as well as insight into xenobiotic disposition during sepsis. TLR4 is critical for the transduction of extracellular LPS signaling into the nucleus in response to Gram-negative bacterial infection. The missense mutation (P712H) in the cytoplamic TIR domain of TLR4, leading to a deficient receptor, makes the C3H/HeJ mouse a useful model to study LPS signaling. As shown in Figs. 1 and 2, TLR4-normal (C3H/OuJ) mice exhibited a dose- and time-dependent decrease in Oatp4 mRNA levels following LPS administration. In contrast, LPS did not produce a statistically significant decrease in Oatp4 mRNA levels at any dose administered or time examined in TLR4-mutant (C3H/HeJ) mice. Therefore, these data suggest that TLR4 is an important mediator in the LPS signaling to down-regulate Oatp4. It is pertinent to emphasize in this context that after LPS administration, mice tend to eat or drink less, and such temporary starvation may have some effects on hepatic gene expression. However, the observed effect of LPS on Oatp4 mRNA expression in this study is not due to such a starvation effect, because if it were, then both C3H/HeJ and C3H/OuJ mice should have exhibited the same results after LPS administration and there should have been no dose- or time-responses.
To date, at least 10 members of the TLR family have been cloned in mammals. TLR2 is known to mediate lipoprotein signaling (Takeuchi et al., 2000), whereas the role of TLR4 in LPS signaling is accepted. However, the role of TLR2 in LPS signaling has been controversial. Recent findings have shown that mice with a targeted deletion of TLR2 have no discernible effect of LPS on signal transduction (Takeuchi et al., 1999). Moreover, commercial LPS preparations from Escherichia coli lose their ability to induce TLR2-dependent responses after removing contaminating proteins in the preparation by multiple phenol extractions. This suggests that phenol-soluble contaminants in commercial LPS preparations are responsible for signaling through TLR2, whereas protein-free bacterial LPS signals only through TLR4 (Hirschfeld et al., 2000). Thus, in TLR4-mutant C3H/HeJ mice, impurities present in the LPS preparation used in this study might have contributed toward the overall response of the LPS-mediated decrease of Oatp4 mRNA.
LPS has a negative effect on the expression of a variety of genes in liver, including genes encoding acute-phase proteins, transport proteins at the sinusoidal and canalicular membranes of hepatocytes, and drug-metabolizing enzymes (Beigneux et al., 2002). LPS-induced cholestasis is thought to be caused by consistent and rapid down-regulation of transporters at the sinusoidal (e.g., Ntcp) (Moseley et al., 1996; Bolder et al., 1997) and canalicular (e.g., Bsep, Mrp2) (Trauner et al., 1997; Vos et al., 1998) membranes of hepatocytes. The liver is a major organ to respond to cytokines, leading to alterations in gene expression. A number of cytokines reach the liver through the blood or are produced by the liver itself in response to systemic LPS and/or cytokines. Thus, the aforementioned studies were complemented by experiments assessing the effect of putative mediators TNF-, IL-1ß, and IL-6 on bile acid transport by intact liver (Whiting et al., 1995; Green et al., 1996), isolated hepatocyte vesicles (Green et al., 1996; Moseley et al., 1996), and cultured hepatocytes (Green et al., 1994). In the present study, significant differences in serum concentrations of TNF-, IL-1ß, and IL-6 between TLR4-normal C3H/OuJ and TLR4-mutant C3H/HeJ mice after LPS administration provides insight into mechanisms underlying the LPS-induced down-regulation of Oatp4 mRNA. In addition, concentrations of cytokines evoked by LPS in vivo would provide a guideline for cytokine treatments to study the effect of cytokines on mouse Oatp4 promoter activity in vitro.
In TLR4-normal C3H/OuJ mice, serum concentrations of TNF-, IL-1ß, and IL-6 were rapidly, markedly, and temporarily increased after LPS administration (Figs. 3, 4, 5). The LPS-stimulated expression of these cytokines in serum preceded the significant decrease in Oatp4 mRNA levels observed at 6 h and the maximal decrease at 12 h after LPS administration. In contrast, the serum concentrations of TNF-, IL-1ß, and IL-6 stimulated by LPS were markedly lower in magnitude and shorter in duration in TLR4-mutant C3H/HeJ mice. Thus, the markedly increased cytokine concentrations in serum correlate well with the significantly decreased Oatp4 mRNA levels after LPS administration to TLR4-normal C3H/OuJ mice. Moreover, the very small increased cytokine concentrations in serum correlate with a very modest decrease in Oatp4 mRNA levels after LPS administration to TLR4-mutant C3H/HeJ mice. This suggests that TNF-, IL-1ß, and IL-6 might mediate the LPS-induced decrease in Oatp4 mRNA levels.
The liver is a major organ to synthesize as well as respond to cytokines. Systemic cytokines can exert their endocrine effects on hepatocytes by altering liver gene expression. Moreover, systemic cytokines are able to activate liver cells (e.g., Kupffer cells) to produce cytokines, leading to high cytokine concentrations in liver sinusoids. These cytokines, in turn, are able to exert their paracrine and autocrine effects on hepatocytes, Kupffer cells, and stellate cells. Several lines of evidence suggest that the effect of LPS on liver is mediated by cytokines: 1) anti-TNF- antibody blocks LPS-induced cholestasis, whereas administration of TNF- mimics the LPS-induced cholestasis; 2) down-regulation of Ntcp can be achieved by administration of TNF- or IL-1ß instead of LPS (Green et al., 1996; Moseley et al., 1996); 3) administration of IL-1ß causes a similar reduction of Oatp1, Oatp2, Bsep, and Mrp2, as does LPS (Hartmann et al., 2002); and 4) IL-6, like LPS, suppresses Oatp1, Oatp2, Mrp2, and Bsep in vivo (Hartmann et al., 2001, 2002). Additionally, it has been shown that hepatocytes respond to these cytokines by alterations in gene expression predominantly at the transcriptional level (Andus et al., 1991; Moshage, 1997). Cytokines are inactivated by mechanisms such as cytokine receptor antagonists and soluble cytokine receptors, leading to restoration of homeostasis. In the present studies, the LPS-induced decrease in Oatp4 mRNA levels recovered between 12 and 48 h after the disappearance of these cytokines, 12 h after LPS administration (Figs. 2, 3, 4, 5). Taken together, these observations suggest that LPS-induced down-regulation of Oatp4 mRNA levels is mediated by TLR4.
Understanding the mechanism underlying LPS-induced down-regulation of Oatp4 is important for elucidating liver dysfunction and functional changes during sepsis. Canalicular Mrp2 mediates transport of glutathione (GSH) and its conjugates from hepatocytes into bile. These compounds are responsible for bile salt-independent bile flow (Johnson et al., 2002). In response to LPS, Mrp2 rapidly moves from the canalicular membrane into the pericanalicular cytoplasm (Dombrowski et al., 2000), and a decrease in Mrp2 mRNA and protein occurs at later times (Trauner et al., 1997). The rapid and profound decrease in Mrp2 activity in the canalicular membrane in response to LPS treatment might result in an increase in intracellular concentrations of GSH. If Oatp4 uses the same driving force as Oatp1, which is driven by efflux of intracellular GSH into blood (Li et al., 1998), LPS-induced down-regulation of Oatp4 would result in a decrease in the efflux of intracellular GSH, in addition to a decrease in the hepatic uptake of bile acids, as well as other endo- and xenobiotics. Thus, a decrease in Oatp4 expression would attenuate hepatic loading of endo- and xenobiotics during sepsis. Moreover, the LPS-induced down-regulation of Oatp4 would help maintain a high concentration of intracellular GSH, which would reduce liver injury produced by LPS-induced free radicals. Therefore, the LPS-induced down-regulation of Oatp4 may be an attempt to provide hepatoprotection during sepsis, through an eventual decrease in hepatic uptake of bile acids and other organic anions, as well as a decrease in efflux of intracellular GSH into blood.
In summary, LPS caused dose- and time-dependent decreases in Oatp4 mRNA levels in TLR4-normal (C3H/OuJ) mice, but not in TLR4-mutant (C3H/HeJ) mice. Therefore, failure of LPS to decrease Oatp4 mRNA levels in TLR4-mutant mice strongly supports the conclusion that TLR4 is an upstream mediator in the signaling pathway leading to the LPS-induced down-regulation of Oatp4. In addition, LPS induced markedly less production of TNF-, IL-1ß, and IL-6 in serum of TLR4-mutant C3H/HeJ mice than in TLR4-normal C3H/OuJ mice, suggesting that cytokines might be mediators of the LPS-induced decrease in Oatp4 mRNA levels. Overall, the down-regulation of Oatp4 by LPS may be responsible for the decrease in Na+-independent hepatic uptake of bile acids and other organic anions including endo- and xenobiotics during sepsis.
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Footnotes |
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ABBREVIATIONS: LPS, lipopolysaccharide; bDNA, branched DNA signal amplification assay; ELISA, enzyme-linked immunosorbent assay; IL; interleukin; Oatp4, organic anion-transporting polypeptide 4; TLR4, Toll-like receptor 4; TNF-, tumor necrosis factor ; Ntcp, Na+/taurocholate-cotransporting polypeptide; Mrp2, multidrug resistance-associated protein 2; Bsep, bile salt export pump; BSP, sulfobromophthalein; TIR, Toll/IL-1 receptor; MyD88/Mal, myeloid differentiation factor 88 (MyD88)-adaptor-like protein; GSH, glutathione.
1 Current address: U.S. Food and Drug Administration, 5100 Paint Branch Parkway, College Park, MD 20740. 
2 Current address: Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel St., Tucson, AZ 85721.
Address correspondence to: Dr. Curtis D. Klaassen, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160. E-mail: cklaasse{at}kumc.edu
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