Stoichiometry based steady-state hepatic flux analysis: computational and experimental aspects.

The liver has many complex physiological functions, including lipid, protein and carbohydrate metabolism, as well as bile and urea production. It detoxifies toxic substances and medicinal products. It also plays a key role in the onset and maintenance of abnormal metabolic patterns associated with various disease states, such as burns, infections and major traumas. Liver cells have been commonly used in in vitro experiments to elucidate the toxic effects of drugs and metabolic changes caused by aberrant metabolic conditions, and to improve the functions of existing systems, such as bioartificial liver. More recently, isolated liver perfusion systems have been increasingly used to characterize intrinsic metabolic changes in the liver caused by various perturbations, including systemic injury, hepatotoxin exposure and warm ischemia. Metabolic engineering tools have been widely applied to these systems to identify metabolic flux distributions using metabolic flux analysis or flux balance analysis and to characterize the topology of the networks using metabolic pathway analysis. In this context, hepatic metabolic models, together with experimental methodologies where hepatocytes or perfused livers are mainly investigated, are described in detail in this review. The challenges and opportunities are also discussed extensively.