![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
The function of hepatic transporters is to move organic substances across sinusoidal and canalicular membranes. During extrahepatic cholestasis, transporters involved in the movement of substances from blood to bile, such as sodium/taurocholate-cotransporting polypeptide (Ntcp) and multidrug resistance protein 2 (Mrp2), are down-regulated, whereas others that transport chemicals from liver to blood, such as Mrp3, are up-regulated. Unlike extrahepatic cholestasis, where transporter expression responds to the stress of accumulating bile constituents, lipopolysaccharide (LPS)-induced intrahepatic cholestasis may be directly caused by alterations in transporter expression. The aim of this study was to quantitatively determine the effect of LPS on transporter expression and study the mechanism(s) by which LPS alters mRNA levels of major hepatic transporters in Sprague-Dawley rats. Hepatic mRNA levels of Mrp2, Mrp6, multiple drug resistance protein 1a (Mdr1a), organic anion-transporting polypeptide 1 (Oatp1), Oatp2, Oatp4, Ntcp, bile salt export pump, organic cation transporter 1 (Oct1), and organic anion transporter 3 (Oat3) were dramatically decreased, beginning approximately 6 h after LPS administration, whereas Mrp5 and Oat2 levels were unchanged. In contrast, LPS increased mRNA levels of Mrp1, Mrp3, and Mdr1b concurrently with the down-regulated transporters. Pretreatment with dexamethasone, which decreases the release of cytokines, reversed the reduction of Mdr1a, Oatp1, Oatp2, Oct1, and Ntcp mRNA following LPS administration. Furthermore, dexamethasone pretreatment also prevented the LPS-mediated increase in Mrp1, Mrp3, and Mdr1b, whereas pretreatment with aminoguanidine or gadolinium chloride, an inhibitor of inducible nitric oxide synthetase and a Kupffer cell toxicant, respectively, had no effect on the LPS-induced changes. The concurrent repression and induction of various transporters, as well as dexamethasone abatement of both LPS-mediated repression and induction, indicates that these responses may be mediated through similar pathways.
This article has been cited by other articles:
|
|
 |
|
  T. Fujita, S. Yasuda, Y. Kamata, K. Fujita, Y. Ohtani, Y. Kumagai, and M. Majima Contribution of Down-Regulation of Intestinal and Hepatic Cytochrome P450 3A to Increased Absorption of Cyclosporine A in a Rat Nephrosis Model J. Pharmacol. Exp. Ther., November 1, 2008; 327(2): 592 - 599. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Le Vee, P. Gripon, B. Stieger, and O. Fardel Down-Regulation of Organic Anion Transporter Expression in Human Hepatocytes Exposed to the Proinflammatory Cytokine Interleukin 1{beta} Drug Metab. Dispos., February 1, 2008; 36(2): 217 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Lickteig, C. D. Fisher, L. M. Augustine, L. M. Aleksunes, D. G. Besselsen, A. L. Slitt, J. E. Manautou, and N. J. Cherrington Efflux Transporter Expression and Acetaminophen Metabolite Excretion Are Altered in Rodent Models of Nonalcoholic Fatty Liver Disease Drug Metab. Dispos., October 1, 2007; 35(10): 1970 - 1978. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Wagner, G. Zollner, P. Fickert, J. Gumhold, D. Silbert, A. Fuchsbichler, J. S. Gujral, K. Zatloukal, H. Denk, H. Jaeschke, et al. Hepatobiliary Transporter Expression in Intercellular Adhesion Molecule 1 Knockout and Fas Receptor-Deficient Mice after Common Bile Duct Ligation Is Independent of the Degree of Inflammation and Oxidative Stress Drug Metab. Dispos., September 1, 2007; 35(9): 1694 - 1699. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Petrovic, S. Teng, and M. Piquette-Miller REGULATION OF DRUG TRANSPORTERS: DURING INFECTION AND INFLAMMATION Mol. Interv., April 1, 2007; 7(2): 99 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Lickteig, A. L. Slitt, M. C. Arkan, M. Karin, and N. J. Cherrington Differential Regulation of Hepatic Transporters in the Absence of Tumor Necrosis Factor-{alpha}, Interleukin-1{beta}, Interleukin-6, and Nuclear Factor-{kappa}B in Two Models of Cholestasis Drug Metab. Dispos., March 1, 2007; 35(3): 402 - 409. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Sarkadi, L. Homolya, G. Szakacs, and A. Varadi Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System. Physiol Rev, October 1, 2006; 86(4): 1179 - 1236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Cifelli and A. C. Ross All-trans-retinoic acid distribution and metabolism in vitamin A-marginal rats. Am J Physiol Gastrointest Liver Physiol, August 1, 2006; 291(2): G195 - G202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Moffit, L. M. Aleksunes, J. M. Maher, G. L. Scheffer, C. D. Klaassen, and J. E. Manautou Induction of Hepatic Transporters Multidrug Resistance-Associated Proteins (Mrp) 3 and 4 by Clofibrate Is Regulated by Peroxisome Proliferator-Activated Receptor {alpha} J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 537 - 545. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Cheng, J. Maher, M. Z. Dieter, and C. D. Klaassen REGULATION OF MOUSE ORGANIC ANION-TRANSPORTING POLYPEPTIDES (OATPS) IN LIVER BY PROTOTYPICAL MICROSOMAL ENZYME INDUCERS THAT ACTIVATE DISTINCT TRANSCRIPTION FACTOR PATHWAYS Drug Metab. Dispos., September 1, 2005; 33(9): 1276 - 1282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Aleksunes, A. M. Slitt, N. J. Cherrington, M. S. Thibodeau, C. D. Klaassen, and J. E. Manautou Differential Expression of Mouse Hepatic Transporter Genes in Response to Acetaminophen and Carbon Tetrachloride Toxicol. Sci., January 1, 2005; 83(1): 44 - 52. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
