ROS and pentose phosphate pathway: mathematical modelling of the metabolic regulation in response to xenobiotic-induced oxidative stress and the proposed Impact of the gluconate shunt
| Autor: | Simone Schmitz-Spanke, Mario Pink, Doris Schittenhelm, Maria Neuss-Radu, Nisha Verma |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Antioxidant medicine.medical_treatment Pentose phosphate pathway medicine.disease_cause Biochemistry Gluconates Xenobiotics Pentose Phosphate Pathway 03 medical and health sciences chemistry.chemical_compound medicine Humans Glycolysis chemistry.chemical_classification Reactive oxygen species 030102 biochemistry & molecular biology General Medicine Glutathione Metabolism Models Theoretical Metabolic pathway Oxidative Stress 030104 developmental biology chemistry Reactive Oxygen Species Oxidative stress |
| Zdroj: | Free radical research. 53(9-10) |
| ISSN: | 1029-2470 |
| Popis: | Elevated intracellular levels of reactive oxygen species (ROS), e.g. resulting from exposure to xenobiotics, can cause severe damages. Antioxidant defence mechanisms, which involve regulation of enzyme activities, protect cells to a certain extent. Nevertheless, continuous or increased exposure can overwhelm this system resulting in an adverse cellular state. To simulate exposure scenarios and to investigate the transition to an adverse cellular state, a mathematical model for the dynamics of ROS in response to xenobiotic-induced oxidative stress has been developed. It is based on exposure experiments of human urothelial cells (RT4) to the nitrated polycyclic aromatic hydrocarbon 3-nitrobenzanthrone (3-NBA), a component of diesel engine exhaust, and takes into account the following metabolic pathways of the antioxidant defence system: glutathione redox cycle scavenging directly ROS, the pentose phosphate pathway and the gluconate shunt as NADPH supplier and the beginning of glycolysis. In addition, ROS generation due to the bioactivation of 3-NBA has been implemented. The regulation of enzyme activities plays an important role in the presented mathematical model. The in silico model consists of ordinary differential equations on the basis of enzyme kinetics and mass action for the metabolism of 3-NBA. Parameters are either estimated from performed in vitro experiments via least-squares fitting or obtained from the literature. The results underline the importance of the pentose phosphate pathway to cope with oxidative stress and suggest an important role of the gluconate shunt during low-dose exposure. |
| Databáze: | OpenAIRE |
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