In fulminant hepatic failure, the clinical use of bioartifical liver support with porcine hepatocytes is the subject of a controversial debate. Cytochrome P450 (CYP) metabolic functions have relevant implications for drug metabolism and detoxification. In this study, we investigate interspecies differences in CYP gene expression between human and porcine primary hepatocytes and the impact of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) exposition mimicking cytokine release in fulminant hepatic failure.

Primary hepatocyte cultures were isolated from human resection specimens and from German landrace pigs. Cell cultures (single and co-cultures) were exposed to porcine vs. human IL-6 and TNF-alpha, respectively. Changes in quantitative CYP gene expression were investigated by semi-quantitative RT-PCR.

Significant differences in species-specific CYP gene expression by human and porcine hepatocytes were found after exposure to species-identical IL-6 (10 ng/ml) for CYP 1A1, CYP 2C, CYP 3A (P = 0.002, 0.022, 0.017, respectively) or species-identical TNF-alpha (30 ng/ml) for CYP 1A2 and CYP 2A (P = 0.037, 0.023, respectively). In single vs. co-culture, human hepatocytes demonstrated stronger repression of CYP 1A1, 2C8 and 3A4 expression after dosage with human IL-6 (10 ng/ml) (P = 0.022, 0.031, 0.014, respectively).

Our findings demonstrate significant species-specific differences in CYP gene expression and regulation when high doses of IL-6 and TNF-alpha are used (10 and 30 ng/ml, respectively). These findings may point to species-specific physiological incompatibilities of porcine hepatocytes and thus limit their clinical versatility.

Liver transplantation has revolutionized the management of acute or fulminant liver failure. Overall success rates of liver transplantation are satisfactory, although not as high as for elective transplantation. Although the bulk of liver transplants use standard whole grafts, interesting data are emerging on auxiliary liver grafts and donations from living donors. Liver transplantation is an integral part of management protocols complementing the sophisticated critical care protocols that have contributed significantly to the overall improved outcomes seen in acute liver failure. The potential for liver support devices to have an impact on the need for liver transplantation and outcomes after transplantation remains exciting.

In fulminant hepatic failure, the use of bioartificial liver support (BAL) with porcine hepatocytes is the subject of a current and controversial debate.1 Specifically, the issue of cross-species physiological incompatibilities has not been addressed so far. We therefore investigated the effects of species-specific cytokines in single and cocultures on hepatocyte function. Hepatocyte cultures were isolated from human resection specimens and from Landrace pigs. Single and cocultures were exposed to porcine and human interleukin (IL)-6 or tumor necrosis factor (TNF)-alpha. Changes in expression of C-reactive protein (CRP), albumin, CCAAT enhancer binding protein (C/EBP)-alpha and C/EBP-beta and metabolic competence of cultured cells was studied by measuring testosterone metabolite production. After human or porcine IL-6 dosing, CRP was induced up to 100-fold in human hepatocyte cultures, while porcine hepatocytes responded marginally (2- to 5-fold). Treatment with human or porcine IL-6 or TNF-alpha resulted in reduced albumin production, albeit at different levels when human and porcine hepatocytes were compared (P = 0.001). Unlike human, porcine hepatocytes produced less of 6alpha-hydroxytestosterone (6alpha-HT) (P < 0.001) and 7alpha-HT (P < 0.001) after human or porcine IL-6 dosing and treatment with species-specific TNF-alpha induced (human hepatocytes) or decreased (porcine hepatocytes) 6beta-HT production (P = 0.021). In coculture with free exchange of metabolites, porcine hepatocytes produced less 6alpha-HT (P = 0.048) and 16alpha-HT (P = 0.033), whereas after treatment with human IL-6 reduced CRP gene and protein expression was observed with human hepatocytes (P = 0.013). In conclusion, species-specific responses of hepatocytes to cytokines and interactions with xenobiotic metabolites may limit the clinical effectiveness of porcine hepatocytes in BAL.

Enthusiasm for liver support devices, particularly cell-based biological systems and albumin dialysis, increased over the last decade and there has been considerable clinical activity both within and without the construct of clinical trials. Most data have been generated on patients with acute liver failure or in patients with decompensation of chronic liver disease, often referred to as acute-on-chronic liver failure. In acute liver failure liver, liver support devices are more realistically being used as a 'bridge' to liver transplantation rather than to transplant-free survival. In acute-on-chronic liver failure the clinical objective of attaining clinical stability with treatment appears more achievable. The so-called bioartificial liver device, based on porcine hepatocytes, is the most extensively evaluated biological device. A sizeable clinical trial failed to demonstrate efficacy, but secondary analyses suggest it would be unwise to assume futility had been established with this device. Molecular adsorbent recirculating system leads the way in the non-biological category in terms of the number of patients treated, but data from large clinical trials are not yet available. One of the strongest conclusions of this review is that the amount of high-quality data available on liver support devices dramatically understates the effort and money that have been expended in their assessment. It is very clear that randomized controlled trials are mandatory to establish clinical efficacy, but it is less clear how the ideal trial should be constructed.