TY - JOUR

T1 - 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

AU - Jorgensen, Anders

AU - Thygesen, Maria Bremholm

AU - Kristiansen, Uffe

AU - Poulsen, Henrik Enghusen

N1 - Publisher Copyright: © 2021 Medisinsk Fysiologisk Forenings Forlag (MFFF).

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - 8-oxo-7,8-dihydro-2-deoxyguanosine

KW - 8-oxo-7,8-dihydroguanosine

KW - DNA

KW - DNA repair

KW - kinetics

KW - oxidative stress

KW - RNA

U2 - 10.1080/00365513.2021.1969682

DO - 10.1080/00365513.2021.1969682

M3 - Journal article

C2 - 34511003

AN - SCOPUS:85114813847

VL - 81

SP - 540

EP - 545

JO - Scandinavian Journal of Clinical & Laboratory Investigation

JF - Scandinavian Journal of Clinical & Laboratory Investigation

SN - 0036-5513

IS - 7

ER -