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An in silico kinetic model of 8-oxo-7,8-dihydro-2-deoxyguanosine and 8-oxo-7,8-dihydroguanosine metabolism from intracellular formation to urinary excretion

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Oxidatively generated DNA damage is of paramount importance in a wide range of physiological and pathophysiological processes. Urinary 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) is often used as an outcome marker in studies on the role of oxidatively generated DNA damage, but its exact relation to intracellular damage levels and variations in DNA repair have been unclear. Using a new approach of quantitative kinetic modeling inspired by pharmacokinetics, we find evidence that in steady state–i.e. when systemic consequences of given change in damage or cellular removal rates have stabilized - the urinary excretion of 8-oxodG is closely correlated to rates of damage and intracellular 8-oxodG levels, but independent of the rate of cellular removal. Steady state was calculated to occur within approximately 12 h. A similar pattern was observed in a model of the corresponding RNA marker 8-oxo-7,8-dihydroguanosine (8-oxoGuo), but with steady-state occurring slower (up to 5 d). These data have significant implications for the planning of studies and interpretation of data involving urinary 8-oxodG/8-oxoGuo excretion as outcome.Highlights The kinetics of 8-oxodG/8-oxoGuo formation, removal and excretion were simulated in silico. The model was based on existing data on 8-oxodG/8-oxoGuo levels and removal/excretion rates. Intracellular 8-oxodG/8-oxoGuo was closely correlated with urinary excretion in steady state. Changes in removal rates did not influence urinary excretion of 8-oxodG/8-oxoGuo.

OriginalsprogEngelsk
TidsskriftScandinavian Journal of Clinical and Laboratory Investigation
ISSN0036-5513
DOI
StatusAccepteret/In press - 2021

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