title: Integrating cellular metabolism into a multiscale whole-body model.
abstract: Cellular metabolism continuously processes an enormous range of external compounds into endogenous metabolites and is as such a key element in human physiology. The multifaceted physiological role of the metabolic network fulfilling the catalytic conversions can only be fully understood from a whole-body perspective where the causal interplay of the metabolic states of individual cells, the surrounding tissue and the whole organism are simultaneously considered. We here present an approach relying on dynamic flux balance analysis that allows the integration of metabolic networks at the cellular scale into standardized physiologically-based pharmacokinetic models at the whole-body level. To evaluate our approach we integrated a genome-scale network reconstruction of a human hepatocyte into the liver tissue of a physiologically-based pharmacokinetic model of a human adult. The resulting multiscale model was used to investigate hyperuricemia therapy, ammonia detoxification and paracetamol-induced toxication at a systems level. The specific models simultaneously integrate multiple layers of biological organization and offer mechanistic insights into pathology and medication. The approach presented may in future support a mechanistic understanding in diagnostics and drug development.
authors.affiliation: Bayer Technology Services GmbH, Computational Systems Biology, Leverkusen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Krauss
authors.forename: Stephan
authors.initials: S
authors.lastname: Schaller
authors.forename: Steffen
authors.initials: S
authors.lastname: Borchers
authors.forename: Rolf
authors.initials: R
authors.lastname: Findeisen
authors.forename: Jörg
authors.initials: J
authors.lastname: Lippert
authors.forename: Lars
authors.initials: L
authors.lastname: Kuepfer
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics; D000493:Allopurinol / Q000008:administration & dosage; D000641:Ammonia / Q000493:pharmacokinetics; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D033461:Hyperuricemia / Q000378:metabolism / Q000628:therapy; D008658:Inactivation, Metabolic / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000502:physiology*; D008660:Metabolism / Q000502:physiology; D008954:Models, Biological; D014508:Urea / Q000378:metabolism; D056806:Urea Cycle Disorders, Inborn; D014527:Uric Acid / Q000378:metabolism
chemical_list: D014527:Uric Acid; D000082:Acetaminophen; D000493:Allopurinol; D000641:Ammonia; D014508:Urea