Radiation-like modification of bases in DNA exposed to tumor promoter-activated polymorphonuclear leukocytes.
Oxygen species generated by human polymorphonuclear leukocytes (PMNs) activated by 12-O-tetradecanoylphorbol-13-acetate (TPA) caused the formation of 5-hydroxymethyl-2'-deoxyuridine (HMdUrd), and (+) and (-) diastereoisomers of cis-thymidine glycol (dTG) in DNA that was exposed to them. There were 9 HMdUrds and 31 dTGs formed per 1 X 10(6) thymidine residues. When Fe(II)/ethylenediaminetetraacetic acid was added to TPA-activated PMNs at 0, 10, 15, and 20 min after TPA, HMdUrd formation increased 5-, 13-, 30-, and 35-fold. Although dTG was initially formed in larger amounts than HMdUrd, it eventually decreased but was still 5-, 6-, 5.5-, and 3-5-fold, respectively, higher than in the absence of iron. From 65 to 1800 times more HMdUrd was formed in DNA when autologous plasma was present during incubation of DNA with TPA-activated PMNs than in its absence. The levels of dTG also varied from about the same as HMdUrd to the nondetectable. Reconstituted human serum transferrin used instead of plasma or Fe(II) also supported the formation of HMdUrd and dTG. When DNA was treated with Fe(II)-reduced H2O2 in the absence of PMNs and TPA, both derivatives were formed. However, the same treatment of marker dTG of dTG-containing polydeoxyadenylic-thymidylic acid caused the decomposition of dTG. Thus, the reduction of hydrogen peroxide by Fe(II) complexed to either ethylenediaminetetraacetic acid or amino acids amy be responsible for the formation of HMdUrd and dTG and for subsequent decomposition of dTG in DNA exposed to the TPA-activated PMNs.
D004247:DNA / Q000378:metabolism; D004249:DNA Damage / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005609:Free Radicals; D006801:Humans; D006878:Hydroxides; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology*; D013237:Stereoisomerism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism
D005609:Free Radicals; D006878:Hydroxides; D014168:Transferrin; C029390:thymidine glycol; C018080:5-hydroxymethyl-2'-deoxyuridine; D004247:DNA; D007501:Iron; D013755:Tetradecanoylphorbol Acetate; D013936:Thymidine