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Am J Physiol Gastrointest Liver Physiol 293: G1078-G1088, 2007. First published September 13, 2007; doi:10.1152/ajpgi.00350.2006
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LIVER AND BILIARY TRACT

Transporters, enzymes, and enalapril removal in a rat (CC531-induced) liver metastatic model

Lichuan Liu, Huadong Sun, Wiqas Y. Valji, and K. Sandy Pang

Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

Submitted 29 July 2006 ; accepted in final form 11 September 2007

Temporal changes in physiological spaces, protein expression of transporters and enzymes, and enalapril removal were appraised in the metastatic liver tumor model developed from male Wag/Rij rats after the intraportal injection of CC531 colon adenocarcinoma cells; sham-operated preparations received PBS. Liver tissue spaces, investigated with multiple indicator dilution technique in liver perfusion studies, were unchanged at week 3 after tumor induction. At week 4, however, the sinusoidal blood volume and albumin Disse space in tumor-bearing livers were slightly lower compared with those of shams. Increased levels of the canalicular ATP transporters, P-glycoprotein, multidrug resistance-associated protein 2 (Mrp2), and bile salt export pump (Bsep) at week 2 (P < 0.05), unchanged levels of Ntcp, Oatp1a1, Oatp1a4, and Mct2, but decreased levels of cytochrome P450 3a2 (Cyp3a2) and glutathione S-transferase (Gst4-4) at week 4 (P < 0.05) were observed in peritumor vs. sham-operated liver tissues with Western blotting. The steady-state extraction ratio of enalapril, a substrate that enters the liver rapidly via Oatp1a1 and primarily undergoes metabolism by the carboxylesterases, was unaffected by liver metastasis at week 4 regardless of its delivery via the portal vein or hepatic artery into the perfused liver preparations.

microcirculation; kinetics


Address for reprint requests and other correspondence: K. S. Pang, Leslie Dan Faculty of Pharmacy, Univ. of Toronto, 144 College St., Toronto, Ontario, Canada M5S 3M2 (e-mail: ks.pang{at}utoronto.ca)






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