title: Metal-mediated oxidative damage to cellular and isolated DNA by gallic acid, a metabolite of antioxidant propyl gallate.
abstract: Propyl gallate (PG), widely used as an antioxidant in foods, is carcinogenic to mice and rats. PG increased the amount of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a characteristic oxidative DNA lesion, in human leukemia cell line HL-60, but not in HP100, which is hydrogen peroxide (H2O2)-resistant cell line derived from HL-60. Although PG induced no or little damage to 32P-5'-end-labeled DNA fragments obtained from genes that are relevant to human cancer, DNA damage was observed with treatment of esterase. HPLC analysis of the products generated from PG incubated with esterase revealed that PG converted into gallic acid (GA). GA induced DNA damage in a dose-dependent manner in the presence of Fe(III)EDTA or Cu(II). In the presence of Fe(III) complex such as Fe(III)EDTA or Fe(III)ADP, GA caused DNA damage at every nucleotide. Fe(III) complex-mediated DNA damage by GA was inhibited by free hydroxy radical (*OH) scavengers, catalase and an iron chelating agent. These results suggested that the Fe(III) complex-mediated DNA damage caused by GA is mainly due to *OH generated via the Fenton reaction. In the presence of Cu(II), DNA damage induced by GA occurred at thymine and cytosine. Although *OH scavengers did not prevent the DNA damage, methional inhibited the DNA damage. Cu(II)-mediated DNA damage was inhibited by catalase and a Cu(I) chelator. These results indicated that reactive oxygen species formed by the interaction of Cu(I) and H2O2 participates in the DNA damage. GA increased 8-oxodG content in calf thymus DNA in the presence of Cu(II), Fe(III)EDTA or Fe(III)ADP. This study suggested that metal-mediated DNA damage caused by GA plays an important role in the carcinogenicity of PG.
authors.affiliation: Department of Environmental and Molecular Medicine, Mie University School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan.
authors.forename: Hatasu
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Shinji
authors.initials: S
authors.lastname: Oikawa
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Hirakawa
authors.forename: Shosuke
authors.initials: S
authors.lastname: Kawanishi
mesh_terms: D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects*; D005707:Gallic Acid / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008670:Metals / Q000737:chemistry*; D018384:Oxidative Stress; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000975:Antioxidants; D008670:Metals; D005707:Gallic Acid