title: A novel mathematical model describing adaptive cellular drug metabolism and toxicity in the chemoimmune system.
abstract: Cells cope with the threat of xenobiotic stress by activating a complex molecular network that recognizes and eliminates chemically diverse toxic compounds. This "chemoimmune system" consists of cellular Phase I and Phase II metabolic enzymes, Phase 0 and Phase III ATP Binding Cassette (ABC) membrane transporters, and nuclear receptors regulating these components. In order to provide a systems biology characterization of the chemoimmune network, we designed a reaction kinetic model based on differential equations describing Phase 0-III participants and regulatory elements, and characterized cellular fitness to evaluate toxicity. In spite of the simplifications, the model recapitulates changes associated with acquired drug resistance and allows toxicity predictions under variable protein expression and xenobiotic exposure conditions. Our simulations suggest that multidrug ABC transporters at Phase 0 significantly facilitate the defense function of successive network members by lowering intracellular drug concentrations. The model was extended with a novel toxicity framework which opened the possibility of performing in silico cytotoxicity assays. The alterations of the in silico cytotoxicity curves show good agreement with in vitro cell killing experiments. The behavior of the simplified kinetic model suggests that it can serve as a basis for more complex models to efficiently predict xenobiotic and drug metabolism for human medical applications.
authors.affiliation: MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, Budapest, 1094, Hungary; Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, 1094, Hungary; Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, 1113, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Tóth
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, 1113, Hungary.
authors.forename: Anna
authors.initials: A
authors.lastname: Brózik
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, 1113, Hungary.
authors.forename: Gergely
authors.initials: G
authors.lastname: Szakács
authors.affiliation: MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, Budapest, 1094, Hungary; Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, 1094, Hungary; Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, 1113, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Sarkadi
authors.affiliation: MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, Budapest, 1094, Hungary; Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, 1094, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Hegedüs
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D003198:Computer Simulation; D004351:Drug Resistance; D006801:Humans; D008658:Inactivation, Metabolic; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008954:Models, Biological; D049490:Systems Biology
chemical_list: D018528:ATP-Binding Cassette Transporters