Therapy of hyperammonemia

Recently, Ghallab and colleagues have identified a novel strategy to reduce hyper-ammonemia in mice (Ghallab et al., 2015). The authors reduced blood ammonia concentrations by infusing a cocktail of glutamate dehydrogenase and its cofactors alpha-ketoglutarate and NADPH. This approach may be clinically relevant, because therapy of hyperammonemia is challenging (Levesque et al., 1999; Enns et al., 2007; Poh and Chang, 2012). Currently hemodialysis is the treatment of choice for reducing strongly elevated blood ammonia concentrations infusion of glutamate dehydrogenase may represent a less invasive alternative. At first glance, therapy of hyperammo-nemia with glutamate dehydrogenase seems counterintuitive. It is known that glutamate dehydrogenase generates ammonia in the periportal comportment of the liver lobule, which is then further metabolized by urea cycle enzymes (Ghallab et al., 2015). Therefore , one may expect that glutamate dehy-drogenase leads to an increase of ammonia instead of reducing its concentration. The hypothesis that glutamate dehydrogenase may detoxify ammonia came from a systems biology approach (Drasdo et al., 2014a). Recently , techniques of spatio-temporal model-ing have been established (Drasdo 2014a,b; Hoehme et al., 2010). These techniques are based on reconstructions of tissue, where the position of each cell is known in a three di-Such models can be used to simulate, for example , the concentration of ammonia and associated metabolites in the liver vein (representing the liver 'outflow') for a given concentration in the portal vein (representing the 'inflow' of blood). Moreover, it can be simulated to which degree induction of liver damage compromises ammonia detoxifica-tion by the liver (Schliess et al., 2014). Using such integrated spatio/temporal-metabolic models, Ghallab and colleagues have shown that the currently known metabolic pathways of ammonia metabolism by urea cycle and glutamine synthetase are not sufficient to explain the experimentally obtained data. Finally, modeling led to the prediction of an adaptive mechanism that occurs under conditions of toxic liver damage: glutamate dehy-drogenase that normally supplies the urea cycle with ammonia switches its catalytic orientation to consume ammonia (Ghallab et al., 2015). Currently, hepatotoxicity represents an intensively studied topic (Campos et al. and in vitro systems are frequently used in