Accumulation of lipid peroxidation-derived DNA lesions in iron-overloaded thalassemic mouse livers: comparison with levels in the lymphocytes of thalassemia patients.
In thalassemia patients, iron overload can stimulate lipid peroxidation (LPO), thereby generating miscoding DNA adducts. Adducted DNA was measured in the lymphocytes of beta-Thal/Hb E patients and healthy controls and in the organs of thalassemic mice. epsilondA, epsilondC and M(1)dG residues were quantified by (32)P-postlabeling-TLC/HPLC. M(1)dG levels in lymphocyte DNA from patients were 4 times as high as in controls, while the increase in epsilondA and epsilondC was not significant. Adducted DNA accumulated in the liver of thalassemic mice having >2.7 mg Fe/g tissue dry weight; DNA adducts and iron were highly correlated. epsilondA was not specifically generated in certain mouse liver cell types as revealed by immunohistochemical staining. We found elevated LPO-induced DNA damage in the liver of thalassemic mouse and in lymphocytes, implicating that massive DNA damage occurs in the liver of thalassemia patients. We conclude that promutagenic LPO-derived DNA lesions are involved in the onset of hepatocellular carcinoma in these patients.
Meerang
Mayura
M
Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Nair
Jagadeesan
J
Sirankapracha
Pornpan
P
Thephinlap
Chonthida
C
Srichairatanakool
Somdet
S
Arab
Khelifa
K
Kalpravidh
Ruchaneekorn
R
Vadolas
Jim
J
Fucharoen
Suthat
S
Bartsch
Helmut
H
D000293:Adolescent; D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D002648:Child; D018736:DNA Adducts; D004249:DNA Damage; D003839:Deoxyadenosines / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D019190:Iron Overload / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015227:Lipid Peroxidation; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D055815:Young Adult; D055544:beta-Globins / Q000502:physiology; D017086:beta-Thalassemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D018736:DNA Adducts; D003839:Deoxyadenosines; D017382:Reactive Oxygen Species; D055544:beta-Globins; D003841:Deoxycytidine; C032221:1,N(6)-ethenodeoxyadenosine; C032222:3,N(4)-ethenodeoxycytidine; D005979:Glutathione Peroxidase