RT Journal Article
SR Electronic
T1 An Ex Vivo Perfusion System Emulating In Vivo Conditions in Noncirrhotic and Cirrhotic Human Liver
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 730
OP 741
DO 10.1124/jpet.112.194167
VO 342
IS 3
A1 Schreiter, Thomas
A1 Marquitan, Guido
A1 Darnell, Malin
A1 Sowa, Jan-Peter
A1 Bröcker-Preuss, Martina
A1 Andersson, Tommy B.
A1 Baba, Hideo A.
A1 Furch, Marcus
A1 Arteel, Gavin E.
A1 Mathé, Zoltan
A1 Treckmann, Jürgen
A1 Gerken, Guido
A1 Gieseler, Robert K.
A1 Canbay, Ali
YR 2012
UL http://jpet.aspetjournals.org/content/342/3/730.abstract
AB Various models are used for investigating human liver diseases and testing new drugs. However, data generated in such models have only limited relevance for in vivo conditions in humans. We present here an ex vivo perfusion system using human liver samples that enables the characterization of parameters in a functionally intact tissue context. Resected samples of noncirrhotic liver (NC; n = 10) and cirrhotic liver (CL; n = 12) were perfused for 6-h periods. General and liver-specific parameters (glucose, lactate, oxygen, albumin, urea, and bile acids), liver enzymes (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, glutamate dehydrogenase, and γ-glutamyl transferase), overall (M65) and apoptotic (M30) cell-death markers, and indicators of phase-I/phase-II biotransformations were analyzed. The measurement readings closely resembled (patho)physiological characteristics in patients with NC and CL. Mean courses of glucose levels reflected the CLs' reduced glycogen storage capability. Furthermore, CL samples exhibited significantly stronger increases in lactate, bile acids, and the M30/M65 ratio than NC specimens. Likewise, NC samples exhibited more rapid phase-I transformations of phenacetin, midazolam, and diclofenac and phase-I to phase-II turnover rates of the respective intermediates than CL tissue. Collectively, these findings reveal the better hepatic functionality in NC. Perfusion of human liver tissue with this system emulates in vivo conditions and clearly discriminates between noncirrhotic and cirrhotic tissue. This highly reliable device for investigating basic hepatic functionality and testing safety/toxicity, pharmacokinetics/pharmacodynamics and efficacies of novel therapeutic modalities promises to generate superior data compared with those obtained via existing economic perfusion systems.