Multi-level modelling of the parallell metabolism of ethanol and retinol, with implications for foetal alcohol syndrome

• Objective: Models of the human metabolism are important for understanding diseases and could serve as a powerful tool in the drug discovery process. The complexity of even a unicellular organism is tremendous and most researchers have therefore limited their modelling efforts to bacteria, or single intracellular pathways. We studied the parallel metabolism of ethanol and retinol in humans, because of its suggested physiological importance for the development of foetal alcohol syndrome. Large ethanol intake will inhibit the conversion of retinol into retinoic acid, which is a crucial transcription factor during embryonic development. In this study the objective was to construct a quantitative model that connects phenotype observations at a population, organic and intracellular level with differences in genotype and ethanol metabolism, for further prediction of the influence on the foetus. Results: We constructed a multiple compartments model, which included a detailed desccription of the ethanol and retinol metabolism in hepatic cells for different genotypes. The model has been validated using published time-series measurements of ethanol, acetaldehyde and acetate concentrations in the blood. This model correctly accounts for differences in geno- and phenotype observed within the human population. Furthermore, the model shows that the retinol metabolism is decreased by ethanol ingestion, both via a reduced intracellular NAD+ concentration, and by an inhibition of alcohol and aldehyde dehydrogenases. Conclusions: We considered the problem of multi-level modelling with a human model for the ethanol and retinol metabolism in different compartments. This links intracellular mechanisms to macroscopic observations. The model explained the connection between geno- and phenotype differences observed at a population level. This model also shows a plausible relationship between ethanol and retinol metabolism for e.g. foetal alcohol syndrome.

Ämnesord

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

Nyckelord

Systems Biology

Publikations- och innehållstyp

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