Genetic changes of hOGG1 and the activity of oh8Gua glycosylase in colon cancer.
oh8Gua glycosylase repairs DNA by removing oh8Gua, a highly mutagenic oxidative DNA adduct. Recently, the gene for human oh8Gua glycosylase (hOGG1) was cloned and several mutational types have been reported. However, the implications of such mutations in human cancer have not been clearly demonstrated. To test the involvement of hOGG1 mutation in colon carcinogenesis, we analysed the genetic changes of hOGG1 and the activity of oh8Gua glycosylase in 15 paired normal and tumorous colon specimens. The activity of antioxidant enzymes (catalase and superoxide dismutase (SOD)) and extent of oxidative cellular damage (oh8Gua and malondialdehyde) were also assessed to compare the oxidative status of normal and tumour tissues. An Arg 154 to His mutation was detected in two tumour samples, but not in the corresponding normal tissues. A Ser 326 to Cys mutation (polymorphism) was found in both the normal and tumour tissues of 3 patients. However, neither the Arg 154 to His mutation nor the polymorphism at codon 326 significantly decreased the oh8Gua glycosylase activity. The mean activity of oh8Gua glycosylase was significantly higher in the tumours than in normal tissues (P=0.022). Antioxidant enzyme activities were decreased (catalase; P=0.004 and SOD; P=0.002), and the extent of oxidative damage correspondingly increased in the tumour tissues (oh8Gua; P=0.007 and malondialdehyde; P=0.046). Although the sample size was limited, these results suggest that the somatic mutation or the polymorphism of hOGG1 is less likely to be involved in colon carcinogenesis. Nevertheless, the greater oxidative DNA damage in the tumour tissues, as a possible result of impaired antioxidant activity, implies an important role for oxygen free-radicals in colon carcinogenesis.
Park
Y J
YJ
Department of Pharmacology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, 110-744, Seoul, South Korea.
Choi
E Y
EY
Choi
J Y
JY
Park
J G
JG
You
H J
HJ
Chung
M H
MH
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics*; D018736:DNA Adducts / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D043382:DNA-Formamidopyrimidine Glycosylase; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009699:N-Glycosyl Hydrolases / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics
D018736:DNA Adducts; C024829:8-hydroxyguanine; D006147:Guanine; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase