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LIVER GRAFTS PRESERVED IN CELSIOR SOLUTION AS SOURCE OF HEPATOCYTES FOR DRUG METABOLISM STUDIES: COMPARISON WITH SURGICAL LIVER BIOPSIES

Unidad de Hepatología Experimental, Centro de Investigación (M.T.D., N.J., G.P., J.V.C., M.J.G.) and Unidad de Cirugía y Transplante Hepático (A.S., J.M.), Hospital Universitario La Fe, Valencia, Spain

Suitability of human liver grafts preserved in Celsior solution (CS) for preparing metabolically competent hepatocyte cultures has been examined. To this end, basal and induced activity and mRNA levels of major hepatic cytochrome P450 (P450) enzymes have been measured. By 24 h in culture, measurable levels of the 10 P450 mRNAs studied were found in all hepatocyte preparations examined, with CYP2E1, CYP2C9, and CYP3A4 mRNAs being the most abundant. Compared with hepatocytes obtained from surgical liver resections (SLRs), lower content of each P450 mRNA was found in hepatocytes from the CS group; however, the relative distribution of individual P450 mRNAs was similar. Similar results were observed after measuring P450 activities. CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2E1, and CYP3A4 activities in hepatocytes from CS-flushed grafts were lower than but comparable with those of cultures prepared from SLRs. No differences in the metabolite profile of testosterone were found. Treatment of hepatocytes from CS-preserved grafts with model P450 inducers shows that 2 µM methylcholanthrene only increased CYP1A1 and CYP1A2 mRNAs (>100-fold over control), 1 mM phenobarbital markedly increased CYP2A6, CYP2B6, and CYP3A4 mRNA content (>7-fold), and 50 µM rifampicin highly increased CYP3A4 mRNA levels (>10-fold), whereas minor effects (<3-fold) were observed in CYP2A6, CYP2B6, and CYP2C9 mRNAs. This induction pattern of P450s was similar, in terms of magnitude, reproducibility, and specificity, to that shown in primary hepatocytes from surgical biopsies. Overall, our results indicate that, cold-preserved in CS, liver grafts constitute a valuable source of human hepatocytes for drug metabolism studies.

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