Oxidative DNA damage in vivo: relationship to age, plasma antioxidants, drug metabolism, glutathione-S-transferase activity and urinary creatinine excretion.
Oxidative DNA modification has been implicated in development of certain cancers and 8-oxodG, the most abundant and mutagenic DNA modification, has for some time been considered a biomarker of this activity. Urinary excretion of 8-oxodG over 24h has been used to estimate the rate of damage to DNA, and animal studies have supported this rationale. Reported determinants include tobacco smoking, heavy exercise, environmental pollution and individual oxygen consumption. Samples from three published studies were used to determine the association of urinary 8-oxodG excretion with age, plasma antioxidants, the glutathione-S-transferase phenotype and the activity of the xenobiotic metabolising enzyme CYP1A2. In the age range 35-65 years, age was not related to urinary 8-oxodG excretion, and there were no relations to either the glutathione-S-transferase phenotype or to the plasma antioxidants: vitamin C, alpha-tocopherol, beta-carotene, lycopene or coenzyme Q10. The activity of CYP1A2 showed a significant correlation in two of the three studies, as well as a significant correlation of 0.26 (p < 0.05) in the pooled data set. Regression analysis of CYP1A2 activity on 8-oxodG indicated that 33% increase in CYP1A2 activity would correspond to a doubling of 8-oxodG excretion. This finding needs to be confirmed in independent experiments. Spot morning urine samples can under certain circumstances be used to estimate 8-oxodG excretion rate provided that creatinine excretion is unchanged (in paired experiments) or comparable (in un-paired experiments), as evaluated from the correlation between 8-oxodG excretion in 24 h urine samples and in morning spot urine samples corrected for creatinine excretion (r = 0.50, p < 0.05). We conclude that 8-oxodG excretion is determined by factors like oxygen consumption and CYP1A2 activity rather than by factors like plasma antioxidant concentrations.
Poulsen
H E
HE
Department of Clinical Pharmacology, Rigshospitalet, University Hospital Copenhagen, Denmark. henrikep@rh.dk
Loft
S
S
Prieme
H
H
Vistisen
K
K
Lykkesfeldt
J
J
Nyyssonen
K
K
Salonen
J T
JT
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D000367:Age Factors; D000368:Aged; D000975:Antioxidants / Q000032:analysis*; D001205:Ascorbic Acid / Q000032:analysis / Q000097:blood; D002338:Carotenoids / Q000097:blood; D003404:Creatinine / Q000652:urine*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004249:DNA Damage; D003718:Denmark; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000652:urine; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D000077276:Lycopene; D008297:Male; D008875:Middle Aged; D004364:Pharmaceutical Preparations / Q000378:metabolism; D012044:Regression Analysis; D019207:beta Carotene / Q000032:analysis / Q000097:blood
D000975:Antioxidants; D004364:Pharmaceutical Preparations; D019207:beta Carotene; D002338:Carotenoids; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003404:Creatinine; D019388:Cytochrome P-450 CYP1A2; D005982:Glutathione Transferase; D003849:Deoxyguanosine; D001205:Ascorbic Acid; D000077276:Lycopene