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

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.