Section: New Results

Liver modeling

Participants : Noémie Boissier, Dirk Drasdo, Géraldine Cellière, Adrian Friebel, Group Heinzle [Univ. Saarbruecken, Germany] , Group Hengstler [IfADo, Germany] , Stefan Hoehme, Tim Johann, Irène Reo [Vignon-Clementel] , Paul Van Liedekerke, Eric Vibert [Hopital Paul Brousse] , Group Zerial [Max-Planck Inst. for Molecular Genetics, Dresden, Germany] , Groups Iflow, Notox, Vln.

Ammonia detoxification after drug-induced damage

Overdosing acetaminophen (APAP) is the main reason for acute liver failure in the US and UK. Overdose of APAP destroys the hepatocytes located in the center of each liver lobule (pericentral damage), the repetitive functional and anatomical tissue units of liver. Human has about a million of such lobules. As a consequence, the blood is not sufficiently detoxified from ammonia, which is toxic to the body and can lead to encephalopathy. In France about 1000 cases of ammonia intoxication each year. In recent papers we demonstrated by an integrated model that the widely accepted key reactions scheme of ammonia detoxification is insufficient to explain ammonia detoxification after pericentral lobule damage and predicted a missing ammonia sink [73] ]. This finding has triggered new experiments leading to the identification of a widely ignored but fundamentally important ammonia sink mechanism We could show by a testing a number of different mechanisms within novel models that this sink mechanism was the only one able to explain the data [15] . The reaction turned out to have the potential to be therapeutically used by injection of a molecular cocktail triggering it. In the animal model death could be prevented using this cocktail hence providing a possible therapy approach for patients suffering from hyperammonemia. [15] . In a follow-up work, further models have been studied and classified by statistical methods to quantify model selection (Cellière et al., in preparation).

Concepts of modeling of liver across all scales: multiscale liver modeling

Based upon developped multiscale concepts [12] , we developped a multi-level spatial temporal multiscale models of APAP (paracetamol, acetaminophen) toxicity and ammonia metabolism. In on of these models we integrated molecular pathways of APAP drug toxicity (PD); in another one, we represented the ammonia detoxification pathway into each individual hepatocyte of an agent-based model that describes the precise liver lobule architecture (compare with [73] ). This allows us to study the impact of space and architecture on the drug toxicity and drug detoxification. We find in certain cases important differences between models that do represent architecture and those that do not (Cellière et al., in preparation).

Predicting in vivo drug toxicity from in vitro data

APAP (paracetamol, acetaminophen) in vitro experiments have been used to calibrate a model of APAP drug toxicity with in vitro data, and modify this model to predict in vivo toxicity. This procedure is aimed at as a general pathway among cosmetic and pharmaceutical companies to eliminate or at least reduce animal experiments and it should allow a better prediction of drug toxicity in human. Three critical differences between in vitro and in vivo settings were stepwise integrated in the model calibrated with in vitro toxicity data to study their impact on in vivo toxicity predictions: (1) The temporal drug exposure profile, (2) the temporal concentration profile of a class of key enzymes, CYP enzymes. Only in hepatocytes in which CYP enzymes are present, APAP is metabolised and downstream apoptosis can occur. (3) The liver architecture, that is responsible for critical differences in the spatial distribution of the drug. The results are in preparation for publication (Cellière et. al., in preparation).

Miscellaneous

In addition, regenerating lobules after partial hepatectomy were analysed by image analysis, and first simulations of blood and bile flow and molecular transport in those lobules simulated.