RESUMO
Iron is essential for the normal development of cellular processes. This metal has a high redox potential that can damage cells and its overload or deficiency is related to several diseases, therefore it is crucial for its absorption to be highly regulated. A fast-response regulatory mechanism has been reported known as mucosal block, which allows to regulate iron absorption after an initial iron challenge. In this mechanism, the internalization of the DMT1 transporters in enterocytes would be a key factor. Two phenomenological models are proposed for the iron absorption process: DMT1's binary switching mechanism model and DMT1's swinging-mechanism model, which represent the absorption mechanism for iron uptake in intestinal cells. The first model considers mutually excluding processes for endocytosis and exocytosis of DMT1. The second model considers a Ball's oscillator to represent the oscillatory behavior of DMT1's internalization. Both models are capable of capturing the kinetics of iron absorption and represent empirical observations, but the DMT1's swinging-mechanism model exhibits a better correlation with experimental data and is able to capture the regulatory phenomenon of mucosal block. The DMT1 swinging-mechanism model is the first phenomenological model reported to effectively represent the complexity of the iron absorption process, as it can predict the behavior of iron absorption fluxes after challenging cells with an initial dose of iron, and the reduction in iron uptake observed as a result of mucosal block after a second iron dose.
Assuntos
Proteínas de Transporte de Cátions/metabolismo , Absorção Intestinal , Ferro/metabolismo , Modelos Teóricos , Animais , Humanos , Mucosa Intestinal/metabolismo , CinéticaRESUMO
Iron is a trace metal, key for the development of living organisms. Its absorption process is complex and highly regulated at the transcriptional, translational and systemic levels. Recently, the internalization of the DMT1 transporter has been proposed as an additional regulatory mechanism at the intestinal level, associated to the mucosal block phenomenon. The short-term effect of iron exposure in apical uptake and initial absorption rates was studied in Caco-2 cells at different apical iron concentrations, using both an experimental approach and a mathematical modeling framework. This is the first report of short-term studies for this system. A non-linear behavior in the apical uptake dynamics was observed, which does not follow the classic saturation dynamics of traditional biochemical models. We propose a method for developing mathematical models for complex systems, based on a genetic programming algorithm. The algorithm is aimed at obtaining models with a high predictive capacity, and considers an additional parameter fitting stage and an additional Jackknife stage for estimating the generalization error. We developed a model for the iron uptake system with a higher predictive capacity than classic biochemical models. This was observed both with the apical uptake dataset used for generating the model and with an independent initial rates dataset used to test the predictive capacity of the model. The model obtained is a function of time and the initial apical iron concentration, with a linear component that captures the global tendency of the system, and a non-linear component that can be associated to the movement of DMT1 transporters. The model presented in this paper allows the detailed analysis, interpretation of experimental data, and identification of key relevant components for this complex biological process. This general method holds great potential for application to the elucidation of biological mechanisms and their key components in other complex systems.