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.

Glutathione S-Transferase M3 Is Associated with Glycolysis in Intrinsic Temozolomide-Resistant Glioblastoma Multiforme Cells

“…In systemic resistance, metabolism is essential for directly destroying the toxic substrate inside the cell. In the metabolism process, the phase I metabolic enzyme cytochrome P450 (CYP) enzymes oxidize the compound into xenobiotic groups, and then, phase II metabolic enzyme GSTs conjugate CYP-oxidized cytoplasmic metabolites into inactive molecules [44]. Therefore, the GST superfamily is one of the crucial functional protein groups involved in the detoxification and systemic resistance of drugs in cells.…”

Application of CellDesigner program for nutrition planning and food safety control

“…Analysis of arsenic metabolism model in liver using CellDesigner It is known from literature that arsenic represents a serious health problem and it is of great importance to increase knowledge about the impact of arsenic on the human body (Cohen et al, 2013). The use of mathematical models ensures the reduction of necessary experiments on living cells and significantly helps in planning targeted experiments (Tóth et al, 2015). According to available literature, the largest share of arsenic in the human body is ingested through drinking water.…”