Abstract
Various models are employed for investigating human liver diseases and for testing new drugs. However, data generated in such models have only limited relevance for the respective in-vivo conditions in humans. We here present an ex-vivo perfusion system utilizing human liver samples that enables to characterize parameters in a functionally intact tissue context. Resected samples of non-cirrhotic and cirrhotic liver (NC: n=10; CL: n=12) were perfused for 6-h periods. General and liver-specific parameters (glucose, lactate, oxygen, albumin, urea, bile acids); liver enzymes (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, glutamate dehydrogenase, γ-glutamyl transferase); overall (M65) and apoptotic (M30) cell-death markers; as well as 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 CL's reduced glycogen storage capability. Furthermore, CL samples exhibited significantly stronger increases in lactate, bile acids, and in the M30/M65 ratio than NC specimens. Likewise, NC samples exhibited more rapid phase-I transformations of phenacetin, midazolam and diclofenac as well as 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 non-cirrhotic and cirrhotic tissue. Employing this highly reliable device for basic hepatologic research and for testing the safety/ toxicity, the pharmacokinetics/ pharmacodynamics and the efficacies of novel therapeutic modalities thus promises to generate superior data compared to those obtained via existing economic perfusion systems.
- Received March 9, 2012.
- Revision received June 1, 2012.
- Accepted June 1, 2012.
- The American Society for Pharmacology and Experimental Therapeutics