title: Accumulation of lipid peroxidation-derived DNA lesions in iron-overloaded thalassemic mouse livers: comparison with levels in the lymphocytes of thalassemia patients.
abstract: 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.
authors.affiliation: Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Mayura
authors.initials: M
authors.lastname: Meerang
authors.forename: Jagadeesan
authors.initials: J
authors.lastname: Nair
authors.forename: Pornpan
authors.initials: P
authors.lastname: Sirankapracha
authors.forename: Chonthida
authors.initials: C
authors.lastname: Thephinlap
authors.forename: Somdet
authors.initials: S
authors.lastname: Srichairatanakool
authors.forename: Khelifa
authors.initials: K
authors.lastname: Arab
authors.forename: Ruchaneekorn
authors.initials: R
authors.lastname: Kalpravidh
authors.forename: Jim
authors.initials: J
authors.lastname: Vadolas
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.forename: Helmut
authors.initials: H
authors.lastname: Bartsch
mesh_terms: 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
chemical_list: 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