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P-glycoprotein function and expression during obstructive cholestasis in rats.
Eur J Gastroenterol Hepatol. 2008 May; 20(5):404-12.EJ

Abstract

OBJECTIVES

The present study was aimed at evaluation of in vivo biliary and renal excretion of rhodamine 123 (Rho123), a P-glycoprotein (P-gp) substrate, in rats during either acute or chronic cholestasis induced by bile duct obstruction (BDO).

METHODS

The Rho123 clearance study was performed either one (BDO1) or seven (BDO7) days after BDO. Bile flow was reconstituted, and bile and urine were collected after steady-state plasma concentration of Rho123 was attained. Tissue expression of P-gp was evaluated by quantitative immunohistochemistry, and immunoblotting.

RESULTS

Significant up-regulation of the liver P-gp protein was observed in acute and chronic cholestasis. Primary periportal location of P-gp was enlarged also to pericentral areas. In the kidneys, immunohistochemistry showed pancellular increase in P-gp after 1 day of BDO, which subsided after 7 days of BDO. Nevertheless, biliary and renal clearances (CL(Bile) and CL(R)) of Rho123 did not reflect the induction of P-gp expression. While CL(Bile) was reduced one day after cholestasis and restored on the seventh day, the CL(R) was preserved in BDO1 group and reduced in BDO7 group without change in glomerular filtration rate. In parallel, biliary and renal clearances of conjugated bilirubin were significantly reduced in both cholestatic groups compared with controls.

CONCLUSION

These findings suggest that extrahepatic cholestasis causes time-dependent changes in elimination of Rho123 which do not exactly reflect alteration of P-gp expression in the rat liver and kidney. These data may help to explain impaired elimination of P-gp substrates after short-term cholestasis that may commonly occur in clinical practice.

Authors+Show Affiliations

Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Hradec Kralove, The Czech Republic. micuda@lfhk.cuni.czNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18403942

Citation

Micuda, Stanislav, et al. "P-glycoprotein Function and Expression During Obstructive Cholestasis in Rats." European Journal of Gastroenterology & Hepatology, vol. 20, no. 5, 2008, pp. 404-12.
Micuda S, Brcakova E, Fuksa L, et al. P-glycoprotein function and expression during obstructive cholestasis in rats. Eur J Gastroenterol Hepatol. 2008;20(5):404-12.
Micuda, S., Brcakova, E., Fuksa, L., Cermanova, J., Osterreicher, J., Hroch, M., Mokry, J., Pejchal, J., Martinkova, J., & Staud, F. (2008). P-glycoprotein function and expression during obstructive cholestasis in rats. European Journal of Gastroenterology & Hepatology, 20(5), 404-12. https://doi.org/10.1097/MEG.0b013e3282f471bf
Micuda S, et al. P-glycoprotein Function and Expression During Obstructive Cholestasis in Rats. Eur J Gastroenterol Hepatol. 2008;20(5):404-12. PubMed PMID: 18403942.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - P-glycoprotein function and expression during obstructive cholestasis in rats. AU - Micuda,Stanislav, AU - Brcakova,Eva, AU - Fuksa,Leos, AU - Cermanova,Jolana, AU - Osterreicher,Jan, AU - Hroch,Milos, AU - Mokry,Jaroslav, AU - Pejchal,Jaroslav, AU - Martinkova,Jirina, AU - Staud,Frantisek, PY - 2008/4/12/pubmed PY - 2008/8/22/medline PY - 2008/4/12/entrez SP - 404 EP - 12 JF - European journal of gastroenterology & hepatology JO - Eur J Gastroenterol Hepatol VL - 20 IS - 5 N2 - OBJECTIVES: The present study was aimed at evaluation of in vivo biliary and renal excretion of rhodamine 123 (Rho123), a P-glycoprotein (P-gp) substrate, in rats during either acute or chronic cholestasis induced by bile duct obstruction (BDO). METHODS: The Rho123 clearance study was performed either one (BDO1) or seven (BDO7) days after BDO. Bile flow was reconstituted, and bile and urine were collected after steady-state plasma concentration of Rho123 was attained. Tissue expression of P-gp was evaluated by quantitative immunohistochemistry, and immunoblotting. RESULTS: Significant up-regulation of the liver P-gp protein was observed in acute and chronic cholestasis. Primary periportal location of P-gp was enlarged also to pericentral areas. In the kidneys, immunohistochemistry showed pancellular increase in P-gp after 1 day of BDO, which subsided after 7 days of BDO. Nevertheless, biliary and renal clearances (CL(Bile) and CL(R)) of Rho123 did not reflect the induction of P-gp expression. While CL(Bile) was reduced one day after cholestasis and restored on the seventh day, the CL(R) was preserved in BDO1 group and reduced in BDO7 group without change in glomerular filtration rate. In parallel, biliary and renal clearances of conjugated bilirubin were significantly reduced in both cholestatic groups compared with controls. CONCLUSION: These findings suggest that extrahepatic cholestasis causes time-dependent changes in elimination of Rho123 which do not exactly reflect alteration of P-gp expression in the rat liver and kidney. These data may help to explain impaired elimination of P-gp substrates after short-term cholestasis that may commonly occur in clinical practice. SN - 0954-691X UR - https://www.unboundmedicine.com/medline/citation/18403942/P_glycoprotein_function_and_expression_during_obstructive_cholestasis_in_rats_ L2 - https://doi.org/10.1097/MEG.0b013e3282f471bf DB - PRIME DP - Unbound Medicine ER -